From biology to the clinic: research evidence and therapeutic advances of TROP2-targeted antibody-drug conjugates in small cell lung cancer

Introduction

In accordance with epidemiological data, lung cancer has been reported as the major driver of cancer mortality in the world, comprising approximately 20% of all cases. The annual number of deaths from lung cancer is approximately 2.5 times greater than the number of deaths from colorectal cancer, which ranks second (1). Small cell lung cancer (SCLC), a highly aggressive lung cancer subtype with a tendency for early metastasis, constitutes about 15% of new lung cancer cases and remains associated with poor overall prognosis. However, in extensive-stage SCLC (ES-SCLC), the introduction of first-line chemoimmunotherapy has improved long-term survival outcomes; in the CASPIAN 3-year update, the estimated 36-month overall survival (OS) rate was 17.6% with durvalumab plus platinum-etoposide versus 5.8% with platinum-etoposide alone (2-4). Although platinum-based chemotherapy combined with immunotherapy has improved first-line treatment outcomes in SCLC, the magnitude of benefit remains limited and difficult to sustain. Current second-line therapies have limited efficacy and significant toxicity. Furthermore, the high molecular heterogeneity of SCLC and the lack of effective targets mean that the use of targeted therapies and epigenetic modulators is still in the exploratory stage. Consequently, approximately 90% of patients experience disease relapse within one year and subsequently progress to treatment-resistant disease, underscoring the urgent need for novel therapeutic strategies for SCLC (5-15).

Trophoblast cell surface antigen 2 (TROP2) is a type I transmembrane glycoprotein that functions as a calcium signal transducer. Due to its independent identification across different research contexts, this molecule has accumulated multiple synonymous designations. These include membrane component chromosome 1 surface marker 1 (M1S1), epithelial glycoprotein-1 (EGP-1), and the gastrointestinal tumor-associated antigen (TAA) GA733-1 (also known as the pancreatic carcinoma marker GA733-1/GA733) (16). Chromosomal mapping has identified its coding sequence within the TACSTD2 gene at 1p32.1 (17,18). Under normal physiological conditions, TROP2 exhibits a tightly regulated expression pattern that is largely confined to epithelial tissues, where it plays a critical role in embryonic organogenesis (19). In contrast to its restricted or absent expression in most normal adult tissues, TROP2 is significantly overexpressed across a spectrum of aggressive carcinomas, notably including SCLC (20-22). TROP2 overexpression promotes tumor aggression by concurrently stimulating a network of pro-oncogenic signals, including the integrin β1/receptor for activated C kinase 1 (RACK1)/focal adhesion kinase (FAK)/Src cascade, calcium flux, epithelial-mesenchymal transition (EMT)-inducing transcription factors, and the extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor kappa B (NF-κB) pathways, thereby enhancing proliferative, invasive, and metastatic capacities (23,24). This specific expression pattern suggests that TROP2 may be an ideal therapeutic target and a key prognostic biomarker for SCLC.

An antibody-drug conjugate (ADC) is composed of a targeting monoclonal antibody (mAb), a linker, and a highly potent cytotoxic payload. It enters cells by specific recognition of TAAs (25) and releases its drugs through enzymatic cleavage after internalization, thereby achieving both highly efficient killing and reducing systemic toxicity (26-32). In recent years, there has been significant progress in the use of ADCs for the treatment of lung cancer, with numerous drugs targeting different receptors entering clinical trials. The clinical validation of this approach is evidenced by a growing arsenal of ADCs against targets such as human epidermal growth factor receptor 2 (HER2) [trastuzumab deruxtecan/T-DXd (33)], HER3 [YL202/BNT326 (34)], and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) [SAR408701 (35)]. Furthermore, targets highly relevant to SCLC, such as delta-like canonical Notch ligand 3 (DLL3) (targeted by rovalpituzumab tesirine) and mesenchymal-epithelial transition factor (c-MET) (targeted by telisotuzumab vedotin), are also under active investigation (36). Given the lack of effective targeted therapies for SCLC and its characteristic high recurrence and poor prognosis, ADCs offer a new therapeutic approach. Among potential targets, TROP2 has become a key focus for ADC development due to its high expression in SCLC tissues and association with disease progression (37). The representative TROP2-targeting ADC, sacituzumab govitecan (SG), has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of breast cancer and urothelial carcinoma. It has demonstrated acceptable safety parameters and a significant anti-proliferative role in multiple studies, including the ASCENT and TROPiCS-03 studies. The phase III ASCENT trial reported that in patients with metastatic triple-negative breast cancer (mTNBC) who had failed to respond to other therapies, SG significantly improved the median progression-free survival (PFS) [5.6 vs. 1.7 months, hazard ratio (HR) =0.41], OS (12.1 vs. 6.7 months), and objective response rate (ORR) (35% vs. 5%), compared to single-agent chemotherapy. In the lung cancer field, the phase II TROPiCS-03 trial evaluated the efficacy and safety of SG for second-line treatment of ES-SCLC. Initial findings, including an ORR of 41.9% and median PFS/OS of 4.4 and 13.6 months, support the further investigation of this agent as a promising and safe therapeutic option for metastatic SCLC (38-41). Another agent under investigation, datopotamab deruxtecan (Dato-DXd), has also demonstrated potent antitumor effects in TROP2-positive NSCLC cell line-derived xenograft (CDX)/patient-derived xenograft (PDX) models and the NCI-N87 model, laying an experimental foundation for ADC applications in lung cancer (42-44). Furthermore, HER2-targeting ADCs have been found effective in HER2-mutant NSCLC (45,46), further supporting the feasibility and promise of the ADC strategy in lung cancer treatment. This progress indicates that TROP2-targeting ADCs have the potential to circumvent the limitations of conventional therapies for SCLC.

This article aims to systematically review recent research on TROP2-targeting ADCs for treating SCLC and discuss future research directions, including investigations into TROP2 structure and function, optimization of combination therapy strategies, and the development of TROP2 testing-based precision treatment models.

Therapeutic predicament in SCLC

Against the backdrop of significant advances in NSCLC treatment, patients with SCLC still face the challenges of poor prognosis and limited therapeutic options (47,48). The IMpower133 trial confirmed that atezolizumab combined with chemotherapy improved OS rates in ES-SCLC (12.3 months) in comparison with chemotherapy alone (10.3 months), leading to its FDA approval as a first-line standard regimen. However, the median OS benefit was limited to approximately 2 months, highlighting the persistent constraints of its clinical benefit (49). Although the subsequent CASPIAN, ASTRUM-005, and CAPSTONE-1 trials extended the median OS in ES-SCLC to approximately 15 months (25,50,51), the magnitude of improvement remains modest when compared with the substantial survival gains achieved in multiple other solid tumors, and has not fundamentally altered long-term survival outcomes. The clinical activity of pembrolizumab monotherapy was characterized in the KEYNOTE-028 and KEYNOTE-158 studies (52), which reported a median OS of 7.7 months and an ORR of 19.3%. The CheckMate032 study (53) further indicated ORRs of 11.6% for nivolumab monotherapy and 21.9% when it was combined with ipilimumab. Overall, immune checkpoint inhibitors have demonstrated limited antitumor activity in the relapsed or refractory SCLC setting, with short-lived responses, and nearly all patients ultimately experience disease progression.

Consequently, the rapid emergence of drug resistance and the lack of validated biomarkers to guide subsequent treatment selection remain central barriers to improving therapeutic outcomes in SCLC.

Structure and function of TROP2

TROP2 is encoded by TACSTD2 located on chromosome 1p32.1 and is synthesized as a precursor featuring a canonical structure. This includes an extracellular domain (ECD; AA27-274) anchored by a transmembrane region (TM; AA275-297) and terminated by an intracellular cytoplasmic domain (ICD; AA298-323), preceded by a hydrophobic leader sequence (AA1-26) for membrane targeting. Functionally, TROP2 operates as a stable dimer, a configuration enabled by its single-pass transmembrane helix that connects the ECD to the ICD. This structural organization provides a mechanistic basis for its function as a cell-surface signaling molecule and supports its accessibility as a therapeutic drug target (54). As illustrated in Figure 1, TROP2 exhibits a canonical type I transmembrane architecture and engages multiple downstream signaling pathways implicated in tumor progression. The intracellular segment of TROP2 harbors a highly conserved motif that binds phosphatidylinositol-4,5-bisphosphate (PIP2), an interaction postulated to be central to the regulation of its signal transduction capacity (55).

Figure 1 Schematic representation of TROP2 structure and its major downstream signaling pathways: TROP2, encoded by the TACSTD2 gene, is a type I transmembrane glycoprotein composed of a hydrophobic signal peptide, an ECD, a TM, and an ICD. TACE-mediated shedding of the ECD promotes β-catenin nuclear translocation, leading to upregulation of cyclin D1 and c-myc and driving cell proliferation. Phosphorylation of Ser303 within the ICD by PKC generates DAG and IP3, which induce Ca²⁺ signaling and activate the ERK1/2-MAPK pathway to promote cell cycle progression. Additionally, TROP2 activates the RACK1-mediated FAK/Src/PAK4 axis, reducing cell adhesion and enhancing migration, thereby facilitating cancer cell invasion and metastasis. DAG, diacylglycerol; ECD, extracellular domain; ERK1/2, extracellular signal-regulated kinase 1/2; FAK, focal adhesion kinase; ICD, intracellular domain; IP3, 1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; PAK4, p21 (RAC1) activated kinase 4; PKC, protein kinase C; Rac1-GTP, Ras-related C3 botulinum toxin substrate 1-guanosine triphosphate; RACK1, receptor for activated C kinase 1; Src, steroid receptor coactivator/Src kinase; TACE, tumor necrosis factor-α-converting enzyme; TM, transmembrane domain.

Previous studies have shown that TROP2 can activate multiple intracellular signaling pathways in tumor cells (56). A serine residue (S303) in the TROP2 ICD is phosphorylated by protein kinase C (PKC), generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The released IP3 interacts with IP3 receptors on the endoplasmic reticulum, increasing the intracellular Ca²⁺ concentration (57). This signaling cascade activates the ERK1/2-mitogen-activated protein kinase (MAPK) axis, which in turn modulates the transcription of downstream cell-cycle regulatory genes. This transcriptional reprogramming ultimately drives aberrant tumor cell proliferation (58). A critical oncogenic mechanism of TROP2 involves its tumor necrosis factor-α-converting enzyme (TACE)-mediated ectodomain shedding. The released ECD fragment accumulates in the nucleus in association with β-catenin, where it functions to upregulate the expression of cyclin D1 and c-Myc. This pathway ultimately subverts normal growth control, enforcing a program of tumor cell self-renewal and hyperplasia (21). In terms of extracellular signaling, TROP2 remodels cell adhesion via the integrin β1-RACK1-FAK-Src axis, specifically, by inducing RACK1 clustering in the membrane and weakening the binding of fibronectin to integrin β1, thereby reducing adhesion and facilitating tumor cell metastasis and dissemination (59). TROP2 drives metastatic dissemination by orchestrating a pro-migratory signaling network, as it promotes p21 (RAC1) activated kinase 4 (PAK4), Src, and FAK phosphorylation, synergizes with phosphorylated protein kinase B (pAkt) signaling, and downregulates Ras-related C3 botulinum toxin substrate 1 bound to guanosine triphosphate (Rac1-GTP) activity. The net effect of this signaling cascade is the suppression of cell-cell adhesion and the potentiation of cell motility, which facilitates cancer cell spread (60-62). Furthermore, both in-vivo and in-vitro studies have found that TROP2 in tumor cells can also promote tumor growth via regulated intramembrane proteolysis (RIP) (24,63). TROP2 has also been implicated in angiogenesis. TROP2 promotes tumor angiogenesis in NSCLC through a dual mechanism: it stimulates the expression of the angiogenic mediators platelet and endothelial cell adhesion molecule 1 (PECAM1) and matrix metallopeptidase 13 (MMP13) and activates the ERK1/2 signaling cascade. The convergence of these signals culminates in the formation of new tumor vasculature (64).

Collectively, TROP2 promotes tumor progression through multiple coordinated mechanisms, including membrane-localized signal transduction, Ca²⁺ pathway activation, regulation of cell adhesion and migration, and remodeling of the tumor microenvironment. Its well-defined cell-surface localization, capacity for internalization, and tumor-selective overexpression provide a strong biological rationale for the application of TROP2-targeting ADCs in SCLC.

Architecture, constituents, and functional mechanism of ADCs

Constituents and architecture of ADCs

The structure of ADCs comprises three key components: a mAb conferring target specificity, a chemical linker that provides stability in circulation, and a potent cytotoxic payload responsible for inducing cell death upon internalization. Selective delivery is achieved by specific binding of the antibody to TAAs (65).

The choice of the target antigen is the primary factor determining efficacy. A key consideration in target antigen selection is a marked differential expression profile, exhibiting high density on the cell surface of tumors while maintaining minimal or negligible expression in normal cells (66). To meet this requirement for specific recognition, mAbs form the backbone of ADCs; more recent recombinant technology has led to the humanization of these IgG antibodies (67).

Structurally, the linker serves as a bridge to bind the cytotoxic payload to mAbs through covalent bonds, and its chemical properties determine the stability of the ADC and the efficient release of the cytotoxic drug at the target site (32). Linkers are categorized into cleavable and non-cleavable types. Cleavable linkers are designed to break in response to specific intracellular microenvironments, such as low pH or cleavage by proteases, enabling site-specific release (67-69). If the released payload is membrane-permeable, it can produce a bystander effect and help maintain killing efficacy in tumors with heterogeneous antigen distribution (70). Non-cleavable linkers require full internalization and lysosomal degradation of the antibody before payload release (71), and the released catabolites often have poor cell permeability, thereby limiting the bystander effect.

Common cytotoxic payloads include tubulin inhibitors, agents that damage DNA, and topoisomerase inhibitors (e.g., camptothecin derivatives) (72). The drug/antibody ratio (DAR) typically ranges between 2 and 8 and should be balanced between efficacy and stability to avoid excessive toxicity (73,74). In SCLC, these design variables are clinically relevant because payload/linker platforms [including topoisomerase I (TOP1) inhibitor-based payloads such as SN-38 or DXd] influence bystander activity, toxicity profiles, and sequencing considerations.

Mechanism of action of ADCs

When the ADC antibody binds to its specific antigen on the tumor cell surface, the complex undergoes receptor-mediated endocytosis and intracellular processing, leading to payload release. The cytotoxic payloads function mainly through induction of DNA damage, suppression of nucleic acid synthesis or transcription by targeting key enzymes such as topoisomerases, or interference with microtubule formation (75-77). If the linker lacks sufficient stability in the plasma or the interstitial fluid, premature release can occur before reaching the target cells, leading to systemic toxicity and off-target effects (78). Alternatively, membrane-permeable cytotoxic components can diffuse into the tumor microenvironment and kill adjacent antigen-negative cancer cells through the bystander effect; while this assists in overcoming intratumoral heterogeneity, it also increases the risk to normal tissues (79). Based on these mechanisms, TROP2-targeting ADCs—particularly those employing membrane-permeable payloads such as SN-38 or DXd—tend to exhibit a more pronounced bystander effect, a property that may confer a therapeutic advantage in SCLC characterized by marked intratumoral heterogeneity (80-84).

Suitability of TROP2-ADC for SCLC

The biological suitability of TROP2-ADCs for SCLC is primarily reflected in three interrelated aspects. First, TROP2 displays membrane-localized expression in a substantial proportion of SCLC tumors and undergoes clathrin-mediated endocytosis into endosomal and lysosomal compartments. This characteristic fulfills the fundamental requirements of target accessibility and intracellular trafficking necessary for effective ADC activity (85,86). As illustrated in Figure 2, upon binding to TROP2 on the tumor cell surface, TROP2-targeted ADCs undergo receptor-mediated internalization and lysosomal processing, enabling intracellular payload release. Second, representative TROP2-targeting ADCs, including SG and Dato-DXd, are capable of efficiently releasing TOP1 inhibitor payloads within tumor cells. Owing to the intrinsic membrane permeability of these payloads, a pronounced bystander effect can be elicited, thereby enhancing tissue-level cytotoxicity in SCLC characterized by marked intratumoral heterogeneity of TROP2 expression (42,80,83). Third, SCLC is typified by a high proliferative rate and pronounced replication stress, together with intrinsic DNA damage response (DDR) vulnerability, particularly in Schlafen family member 11 (SLFN11)-high subsets. This molecular background confers heightened sensitivity to TOP1 inhibitor-induced replication fork collapse and DNA double-strand breaks, thereby potentially reducing the risk of cross-resistance with conventional cytotoxic therapies (87). In addition, accumulating evidence indicates that the insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays a critical role in SCLC proliferation, with elevated IGF-1R expression observed in SCLC cell lines (88). Mechanistic studies in non-small cell lung cancer (NSCLC) tumor models have suggested potential crosstalk between TROP2 and growth factor signaling pathways (including IGF-axis signaling). However, direct evidence that TROP2 drives SCLC phenotypes through these mechanisms remains limited, and the relevance of such interactions in SCLC should currently be regarded as hypothesis-generating pending dedicated functional validation in SCLC models (89,90).

Figure 2 Mechanism of TROP2-targeted antibody-drug conjugates: ADCs comprise a monoclonal antibody that specifically recognizes tumor-associated antigens, a linker that governs in-vivo stability and release kinetics, and a cytotoxic payload. After selective binding to TROP2-overexpressing cells, the complex undergoes receptor-mediated endocytosis into endosomes and traffics to lysosomes. Cleavable linkers are severed in acidic or protease-rich compartments, whereas non-cleavable linkers require proteolysis of the antibody backbone before payload liberation. Released agents—such as microtubule inhibitors (e.g., auristatin) or topoisomerase-I inhibitors—disrupt microtubules or enter the nucleus to induce DNA damage, triggering apoptosis and thereby enabling precise tumor killing. Membrane-permeable payloads can diffuse extracellularly and enter adjacent tumor cells, eliciting a “bystander effect” that improves control of antigen-heterogeneous tumors but may increase exposure of normal tissues. Representative TROP2-targeted ADCs depicted include SG (sacituzumab govitecan carrying SN-38), Dato-DXd, and the investigational SHR-A1921, DB13051, and BNT325, exemplifying the core sequence: target recognition → endocytosis → lysosomal release → cytotoxic action → bystander diffusion. ADC, antibody-drug conjugate; Dato-DXd, datopotamab deruxtecan; SG, sacituzumab govitecan; SN-38, 7-ethyl-10-hydroxycamptothecin; TROP2, trophoblast cell surface antigen 2.

Collectively, the membrane-localized and internalizable nature of TROP2, the bystander effect conferred by TOP1-based payloads, and the intrinsic DDR vulnerability of SCLC together establish a three-component coupling framework—linking target expression, payload mechanism, and tumor context—that provides a coherent biological rationale for the clinical activity of TROP2-ADCs in SCLC.

Clinical research progress of TROP2-ADCs in treating SCLC

ADCs targeting TROP2 are becoming a key focus in SCLC treatment; however, investigating the application of TROP2-ADCs in treating SCLC is still in its early stages. This section discusses recent investigations of combination strategies involving the use of TROP2-ADCs for SCLC treatment.

SG

Details of the clinical trials involving SG are summarized in Table 1.

IMMU-132-01 (I/II)

This clinical trial was a multicenter, open-label, single-arm phase I/II basket study with an SCLC expansion cohort, sponsored by Immunomedics. It aimed to evaluate the safety and ORR of SG in previously treated patients with metastatic SCLC (95). The trial did not screen patients based on TROP2 expression but enrolled patients who had received multiple prior lines of therapy. The enrolled patients received intravenous SG at doses of 8 or 10 mg/kg on days 1 and 8 of each 21-day cycle [every 3 weeks (Q3W)] until disease progression or unacceptable toxicity. At the 10 mg/kg dose level, the regimen achieved a median OS of 7.1 months and a median PFS of 3.7 months in 62 previously treated SCLC patients. The observed ORR was 17.7%, with a median duration of response (DOR) of 5.7 months. Tumor shrinkage was observed in 60% of cases. The observed adverse effects with grade III ≥ were primarily fatigue (13%), neutropenia (34%), anemia (6%), and diarrhea (9%). The observed trend linking first-line chemosensitivity to enhanced second-line efficacy, while promising, remains provisional until substantiated by broader prospective studies. Notably, no treatment-related deaths were reported, indicating that SG was well-tolerated and had a manageable safety in this SCLC population.

The TROPiCS-03 phase II basket trial

The TROPiCS-03 study, sponsored by Gilead Sciences, employed a multicenter, open-label, phase II basket design to investigate SG as a second-line monotherapeutic agent, with a primary focus on its efficacy and safety profile. Key inclusion criteria for the trial were: (I) a histological confirmation of ES-SCLC; (II) documented disease progression following a maximum of one prior platinum-based chemotherapy regimen combined with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (III) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and (IV) the presence of measurable lesions according to standard oncological guidelines. Exclusion criteria comprised: (I) prior exposure to topoisomerase I inhibitors, with the exception of etoposide administered during first-line platinum therapy; (II) active, untreated metastases in the central nervous system; or (III) a diagnosis of carcinomatous meningitis. Patients received intravenous SG at 10 mg/kg on days 1 and 8 of each 21-day cycle until disease progression, unacceptable toxicity, or other withdrawal criteria were met. The primary endpoint was investigator-assessed ORR. Key secondary endpoints included blinded independent central review (BICR)-assessed ORR, DOR, and PFS, as well as OS and safety. Analyses were stratified by platinum sensitivity and platinum resistance. Among 43 enrolled patients with a median follow-up of 12.3 months, the ORR was 41.9% [95% confidence interval (CI): 27.0–57.9%], all of which were partial responses (PRs). The disease control rate (DCR) was 83.7%, and the clinical benefit rate (CBR) was 48.8%. The median time to response (TTR) was 1.4 months. The DCR was 83.7% (95% CI: 69.3–93.2%), the median PFS was 4.40 months (95% CI: 3.81–6.11), and the median OS was 13.60 months (95% CI: 6.57–14.78). The median DOR was 4.73 months (95% CI: 3.52–6.70). The BICR results were consistent with the investigator’s assessments. Clinical outcomes stratified by platinum sensitivity showed that platinum-sensitive patients (n=23) experienced superior efficacy, with an ORR of 47.8% and median OS of 14.7 months, compared to a 35.0% ORR and 6.6-month median OS in the platinum-resistant subgroup (n=20). The safety profile was characterized by grade ≥ III adverse effects that were predominantly hematological, with anemia (5%) and neutropenia (44%) being most common, alongside non-hematological toxicities such as fatigue (2%) and diarrhea (9%). Serious treatment-emergent adverse events (TEAEs) occurred in 51.2% of patients. A single fatal TEAE was reported, which was attributed to neutropenic sepsis. There were no treatment discontinuations due to adverse events. Overall, the TROPiCS-03 study demonstrated a notably high ORR and a manageable safety profile for SG as second-line monotherapy in previously treated patients with ES-SCLC. In the clinical context of limited prior treatment options and the absence of an established standard second-line regimen, these findings provide critical “proof-of-concept” evidence supporting the further development of TROP2-targeting ADCs in SCLC (92). On the basis of these results, Trodelvy^® (SG-hziy) was granted Breakthrough Therapy designation by the U.S. FDA on December 17, 2024 for the treatment of adult patients with ES-SCLC whose disease has progressed on or after platinum-based chemotherapy (authoritative public announcement by the sponsor) (96).

EVOKE-SCLC-04 (NCT06801834)

EVOKE-SCLC-04 (NCT06801834) is an ongoing global, multicenter, randomized, open-label Phase III clinical study sponsored by Gilead Sciences. It aims to compare the efficacy and safety of the ADC SG with standard-of-care chemotherapy, primarily topotecan, in ES-SCLC patients who have undergone radiographic progression after first-line platinum-based therapy with or without a PD-(L)1 inhibitor. Eligible patients are required to have an ECOG performance status of 0–1 and measurable lesions [Response Evaluation Criteria in Solid Tumors (RECIST) 1.1]. Patients with stable, treated brain metastases are allowed, while those with a chemotherapy-free interval of less than 30 days or prior exposure to topoisomerase I inhibitors are excluded. The experimental group receives SG (10 mg/kg intravenously on days 1 and 8 of each 21-day cycle), while the control group is given standard chemotherapy. Treatment continues until disease progression or unacceptable toxicity. The co-primary endpoints are ORR (assessed by BICR) and OS. Key secondary endpoints include PFS, DOR, and safety. Based on the activity demonstrated in the Phase II TROPiCS-03 study, the U.S. FDA granted Breakthrough Therapy designation to Trodelvy^® (SG-hziy) on December 17, 2024 for adult patients with ES-SCLC whose disease has progressed on or after platinum-based chemotherapy (96). Importantly, Breakthrough Therapy designation is intended to facilitate expedited development and review and does not constitute marketing authorization; therefore, SG remains investigational for ES-SCLC. EVOKE-SCLC-04 is an ongoing, global, randomized Phase III confirmatory study designed to generate evidence to support potential regulatory submissions; according to the sponsor-maintained trial record, the study is currently enrolling/recruiting patients and is expected to be completed in October 2029 (93). Collectively, EVOKE-SCLC-04 will help define whether SG can improve clinically meaningful outcomes and inform its potential positioning as a later-line treatment option in ES-SCLC.

NCT04826341

The National Institutes of Health/National Cancer Institute (NIH/NCI)-sponsored Phase I/II basket study (NCT04826341) was designed to explore the therapeutic potential of the ADC SG when co-administered with the ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib, targeting DDR pathways in refractory solid malignancies. The trial aims to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of the combination in the Phase I portion. The Phase II portion will involve evaluation of the ORR in a variety of tumor cohorts, including recurrent SCLC, extrapulmonary small cell neuroendocrine carcinoma, and homologous recombination deficiency-positive solid tumors resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The treatment regimen involves administration of SG on days 1 and 8, combined with berzosertib on days 2 and 9, of each 21-day cycle. The primary endpoints include safety/dose determinations in Phase I and cohort-specific ORR assessments in Phase II. The study also explores replication stress and related biomarkers. Currently recruiting, this trial aims to validate the synthetic lethality strategy of targeting the DDR pathway in combination with a topoisomerase I inhibitor payload. This strategy is expected to validate a “synthetic lethality” approach that combines DDR pathway-targeting agents with TOP1 payload-based ADCs, thereby providing important evidence for combination treatment paradigms involving TROP2-ADCs in SCLC.

Dato-DXd-NCT03401385

NCT03401385 (TROPION-PanTumor01) is a multicenter Phase I study designed to evaluate the safety, tolerability, and preliminary efficacy of the novel TROP2-targeting ADC, Dato-DXd, in the treatment of advanced-stage solid tumors, including SCLC. The specific requirements for inclusion in the SCLC cohort were that patients had undergone therapy involving platinum-based chemotherapy and an immune checkpoint inhibitor, and had received no prior treatment with topotecan or irinotecan. Other inclusion criteria included measurable lesions (RECIST 1.1), ECOG 0–1, adequate organ function, and left ventricular ejection fraction ≥50%, while there was no minimum TROP2 expression requirement for the trial. The exclusion criteria were prior treatment with a deruxtecan-based ADC, active interstitial lung disease (ILD) requiring intervention, and uncontrolled brain metastases. The primary endpoints were the MTD and the recommended dose for expansion (RDE). The secondary endpoints included ORR, DOR, PFS, OS, and pharmacokinetic and immunogenicity profiles. Although specific data for the SCLC cohort have not yet been published. However, the antitumor activity signals observed with Dato-DXd in other TROP2-positive solid tumors, together with its DXd payload and pronounced bystander effect, provide both pharmacological and cross-tumor support for its further development in SCLC.

SHR-A1921 (NCT05154604)

The novel ADC SHR-A1921 utilizes a proprietary IgG1 antibody directed against TROP2 and is linked to a topoisomerase I inhibitor payload (SHR9265) using a tetrapeptide-based cleavable linker. A key innovation lies in the payload itself; SHR9265 demonstrates a superior profile characterized by improved stability, higher binding affinity, longer half-life in circulation, a marked bystander effect, and enhanced in vivo efficacy compared to related agents (20). Clinically, the SCLC expansion cohort within the multicenter, open-label, Phase I first-in-human (FIH) study NCT05154604, sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd., evaluated the safety and preliminary antitumor activity of SHR-A1921. Enrolled patients with ES-SCLC received the recommended exploratory dose of 3.0 mg/kg via intravenous infusion once Q3W. The primary efficacy endpoint was the ORR, while the secondary endpoints included DOR and PFS. Adverse events were systematically recorded. According to data disclosed at World Conference on Lung Cancer (WCLC) 2024, among 15 evaluable SCLC patients, the ORR was 33.3% (95% CI: 15.2–58.3%) and the DCR was 66.7% (95% CI: 41.7–84.8%). The median DOR was 4.4 months (95% CI: 2.3–not reached), and the median PFS was 3.8 months, with a median follow-up time of 5.3 months. Responses were observed even in a population with generally low TROP2 expression. The safety profile was manageable overall. These results suggest promising ORR and antitumor activity in previously treated patients with ES-SCLC. The results require validation in randomized controlled trials. Nevertheless, randomized controlled trials are still required to further confirm its therapeutic advantage and to explore the relationship between TROP2 expression levels, additional biomarkers, and clinical efficacy.

Research progress in other TROP2-ADCs in solid tumor treatment

The clinical development landscape of other TROP2-targeting ADCs in SCLC and solid tumors is summarized in Table 2.

DB-1305/BNT325 (NCT05438329)

BNT325/DB-1305 is a novel TROP2-targeting ADC based on a third-generation topoisomerase-I inhibitor payload. It was constructed using the proprietary DualityBio DITAC platform. The NCT05438329 clinical study is a global Phase I/IIa FIH trial employing a dose-escalation and dose-expansion design. Patients with advanced/metastatic solid tumors who have failed standard therapy, including a specific lung cancer cohort, are enrolled. The primary endpoints include safety, tolerability, dose-limiting toxicities, MTD, and RDE. The secondary endpoints are ORR, DOR, PFS, OS, and immunogenicity. Based on early efficacy results from the NCT05438329 study, DB-1305/BNT325 received an FDA Fast Track designation in January 2024. Although SCLC-specific clinical data have not yet been reported, its cross-tumor activity and next-generation payload design offer a representative example of the “platform-based” development strategy for TROP2-targeting ADCs.

BAT-8008

BAT-8008 is a novel TROP2-targeting ADC utilizing exatecan, a topoisomerase I inhibitor, as its payload. A combination study (NCT06341114: BAT8008 + BAT1308) is currently registered. The administration regimen is Q2W (with a 21-day first cycle followed by 14-day subsequent cycles), with exploration of doses between 0.8 and 2.7 mg/kg. The study aims to evaluate the safety, tolerability, and pharmacokinetic profile of this combination in patients with advanced solid tumors. The primary endpoints include safety and the RP2D, while efficacy indicators such as ORR will also be explored. As a basket trial without a predefined SCLC cohort, the study includes patients with a range of solid malignancies. To date, there has been no release of evidence specific to SCLC. Moreover, its use of an exatecan-based payload provides a conceptual framework for further expanding the payload repertoire of TROP2-ADCs.

OBI-992

OBI-992 is a novel ADC composed of a humanized anti-TROP2 antibody (R4702), a cleavable enzyme-sensitive linker, and the cytotoxic payload exatecan (a Topo-I inhibitor). Conjugation at specific cysteine sites on the antibody further enhances its stability in the circulation. Preclinical evaluations have verified its advantages, demonstrating enhanced serum stability, higher drug delivery efficiency, superior anti-tumor activity, and lower off-target toxicity compared to Dato-DXd. Its maximum non-severely toxic dose is ≥60 mg/kg, indicating promising potential for further clinical development (104,105). The Phase I/II FIH trial (NCT06480240) is designed to determine the MTD/RP2D using dose escalation and will expand to evaluate ORR, DOR, PFS, and OS in patients with advanced solid tumors. To date, evidence specific to SCLC is still awaited. Collectively, these studies underscore, from another perspective, the critical importance of optimizing conjugation sites and payload combinations to improve the therapeutic index of TROP2-ADCs.

JS-108

JS-108 is a TROP2-directed ADC engineered from a humanized mAb specific for TROP2, which is site-specifically conjugated to the cytotoxic agent Tub196 via a hydrolysis-resistant linker designed to enhance plasma stability. A joint development effort between Hangzhou DAC Biotech Company Ltd. and Shanghai Junshi Bioscience Co., Ltd. is advancing this ADC for the treatment of TROP2-expressing malignancies, notably including SCLC. Tub196 is a tubulin B analog with potential anti-tumor activity; it binds to microtubules within cells, triggering apoptosis and reducing tumor cell proliferation. The clinical trial assessing JS-108, NCT04601285, received approval to proceed to clinical stages in July 2020, and the first patient was dosed in November 2020. This FIH, open-label, Phase I trial is designed with sequential segments for dose escalation, cohort expansion, and indication exploration in participants with advanced solid malignancies, such as SCLC. The objectives of the clinical trial are to characterize the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of JS-108. To date, detailed safety/efficacy results from this Phase I study have not been disclosed, and its current status is “Sponsor Adjusted Research Development Plan” (21). As one of the few TROP2-targeting ADCs employing a microtubule inhibitor payload, JS-108 may offer an alternative therapeutic option for patients with SCLC who are unable to tolerate TOP1 inhibitor-associated toxicities, should its clinical activity be confirmed.

Discussion

The integration of immunotherapy with platinum-based chemotherapy has led to meaningful improvements in survival outcomes for patients with SCLC; however, the overall prognosis remains poor, and there is still a lack of reliable biomarkers capable of effectively evaluating first-line treatment efficacy or guiding subsequent therapeutic decisions. Although TROP2-targeting ADCs have introduced a novel therapeutic avenue beyond conventional chemotherapy and immunotherapy—and have achieved regulatory approval in several solid tumors, such as triple-negative breast cancer (82) and urothelial carcinoma (106), thereby validating the therapeutic potential of this target—the application of TROP2-ADCs in SCLC continues to face three major challenges: (I) heterogeneity of tumor antigen expression; (II) the balance between toxicity profiles and deliverable dose intensity; and (III) mechanisms of primary and acquired resistance.

First, heterogeneity in tumor antigen expression represents a critical limiting factor affecting the consistency and durability of responses to TROP2-ADCs. TROP2 expression varies substantially across different tumor types, between distinct regions within the same tumor, and among metastatic lesions. In addition, intrinsic heterogeneity within SCLC is influenced by molecular subtypes, with higher TACSTD2 expression observed in the SCLC-Y and SCLC-P transcriptional subtypes (107), this heterogeneity may result in differential sensitivity to TROP2-ADC therapy across lesions within the same patient. From a translational perspective, these observations highlight the need to incorporate spatial heterogeneity into future trial designs and real-world treatment frameworks. Conventional immunohistochemistry (IHC)-based stratification derived from single-site biopsies may be insufficient to represent whole-body tumor burden, underscoring the necessity for dynamic, whole-body approaches to assess and stratify TROP2 expression.

Second, ADC-associated toxicities constitute an important constraint on sustainable dose intensity and therapeutic window, and the toxicity profile is strongly dictated by the payload/linker platform, thereby determining monitoring and management strategies. For example, SN-38-based SG is commonly associated with hematologic toxicity and gastrointestinal adverse events (e.g., neutropenia and diarrhea), for which prophylactic or early interventions such as granulocyte colony-stimulating factor (G-CSF) support and antidiarrheal therapy can be clinically valuable (108). In contrast, deruxtecan/exatecan (DXd) TOP1 payload ADCs (including TROP2-directed DXd platforms in lung cancer development) carry a clinically important risk of ILD/pneumonitis, which requires distinct vigilance and standardized algorithms (109,110). In lung cancer populations, ILD incidence has been most prominent with trastuzumab deruxtecan (T-DXd) in NSCLC (e.g., ~26% any-grade ILD/pneumonitis reported in DESTINY-Lung01, including fatal cases), whereas ILD rates reported for Dato-DXd have generally been lower but remain clinically relevant and warrant proactive monitoring (111-114). Recognized risk factors for DXd/exatecan-associated ILD/pneumonitis include pre-existing interstitial lung abnormalities/ILD, prior thoracic radiation or lung surgery, reduced baseline pulmonary reserve, and other clinical factors that increase susceptibility to inflammatory lung injury; accordingly, recommended practice includes baseline assessment [pulmonary history, symptom review, and baseline chest computed tomography (CT)/high-resolution computed tomography (HRCT) when feasible], serial symptom screening at each visit, and interval imaging as clinically indicated (110,115). Management follows a ‘hold-evaluate-treat’ paradigm consistent with published guidance and product labeling: at suspected grade 1 (asymptomatic radiographic) ILD, treatment should be interrupted, comprehensive evaluation (including high-resolution imaging and pulmonology input) should be performed, and early corticosteroids should be considered; for grade ≥2 ILD (symptomatic), DXd/exatecan ADC therapy should be permanently discontinued and prompt systemic corticosteroids initiated with an appropriate taper (110,115). In this context, the ‘5S’ strategy (screening, scanning, synergy, suspension, and steroids) represents an operational framework aligned with these ILD mitigation principles and has been associated with reductions in fatal ILD in DXd programs (116). Importantly, toxicity management should not be regarded solely as a supportive care issue but rather as a factor that feeds back into ADC structural optimization and clinical deployment. In the SCLC population, achieving an optimal balance between preserving the bystander effect and minimizing systemic exposure and predictable, platform-specific toxicities will be a key determinant of whether TROP2-ADCs can be advanced into earlier lines of therapy.

Third, resistance remains a major unresolved challenge for TROP2-ADC therapy. Beyond general mechanisms shared across ADCs, resistance to TROP2-directed ADCs can arise at multiple steps along the ADC pharmacology cascade, including antigen modulation, internalisation/trafficking, lysosomal processing, payload efflux, and payload-target (TOP1) alterations. At the antigen level, selective pressure may enrich for subclones with reduced or heterogeneous TROP2 expression or antigen alterations that decrease productive binding and uptake. Consistent with this concept, acquired resistance to SG has been associated with parallel genomic alterations involving both TACSTD2/TROP2 (e.g., T256R) and TOP1 (e.g., E418K), indicating that antigen- and payload-related mechanisms can co-exist under therapy (40). At the intracellular delivery step, impaired receptor-mediated uptake, altered endosomal sorting, or enhanced recycling can reduce lysosomal delivery and payload liberation; similarly, compromised lysosomal function (e.g., reduced acidification or protease activity) may attenuate linker cleavage and/or antibody catabolism required for efficient drug release (117). Downstream, upregulation of ATP-binding cassette transporters (e.g., ABCG2/BCRP) can promote payload efflux and decrease intracellular exposure to camptothecin derivatives such as SN-38; notably, ABC transporter inhibition has been shown to restore SN-38 sensitivity and improve the activity of an SN-38-conjugated anti-TROP2 ADC (IMMU-132) in resistant models (118). Finally, because several TROP2-ADCs employ TOP1 inhibitor payloads, TOP1-pathway resistance may attenuate efficacy and contribute to cross-resistance among sequential TOP1-payload ADCs (119). From the perspective of SCLC biology, key oncogenic pathways—including YAP1, NOTCH, Wnt family signaling, and MYC—have been implicated in therapeutic resistance (120-122). Collectively, these findings suggest that resistance to TROP2-ADCs is unlikely to be driven by a single mechanism; rather, it likely reflects convergent alterations in target availability, intracellular processing, payload exposure, and DDR adaptation.

In terms of patient selection and efficacy monitoring, the ORR in SCLC remains lower than that in metastatic TNBC. Conventional TROP2 detection is limited by tissue sample availability and spatial heterogeneity. Anti-TROP2 aptamer positron emission tomography (PET) imaging, currently under development, enables whole-body, quantitative assessment of TROP2 expression following intravenous administration, potentially optimizing both patient selection and efficacy prediction (123). Notably, experience from NSCLC development suggests that TROP2 often functions as a broad therapeutic target rather than a stringent exclusion biomarker, and a similar paradigm may apply to SCLC, where TROP2-directed ADCs could be deployed across clinically defined populations while emerging tools refine enrichment strategies (109). Future efforts involving chemical modifications of aptamers, together with long-half-life radionuclide labeling to enable long-term TROP2 monitoring and even theranostic applications, could further enhance the precision and effectiveness of SCLC treatment.

Importantly, emerging pre-clinical and translational data in SCLC support the biological feasibility of TROP2-directed strategies. Recent analyses of SCLC cell lines and patient specimens have shown that TACSTD2 (TROP2) expression is present but heterogeneous, varying across tumors, within tumors, and across disease sites, with lower expression observed in some brain metastasis samples (14). These findings reinforce both the rationale for TROP2-targeted ADCs and the need for biomarker-informed patient selection and longitudinal target assessment. In parallel, pre-clinical SCLC models have demonstrated the feasibility of TROP2-directed molecular imaging to identify Trop-2-positive tumors and may facilitate image-guided anti-TROP2 therapeutic strategies, providing additional proof-of-concept for targetability in SCLC (38). However, it should be noted that, in currently available SCLC pre-clinical studies, the evidence primarily supports the utility of TROP2 as a therapeutic vehicle (targetability) rather than providing definitive evidence that it functions as a phenotypic driver in SCLC biology.

From a clinical and translational perspective, the future role of TROP2-targeted agents in SCLC will likely depend not only on single-agent activity but also on rational therapeutic positioning and combination design. First, TROP2-directed ADCs should be considered in a platform-aware manner, as payload/linker technologies may influence efficacy patterns (including bystander effects and resistance liabilities) as well as toxicity profiles, thereby affecting treatment sequencing and combinability (79,124). Second, given the prominent replication stress and DDR dependencies in SCLC, combinations designed to augment DNA damage or impair DDR signaling represent a mechanistically grounded strategy; in this context, SG plus ATR inhibition (berzosertib) provides a clinically relevant proof-of-concept for rational ADC-based combination development (125). Third, combinations with immunotherapy or other systemic modalities may also be of interest in selected settings, but should be pursued cautiously with careful attention to overlapping toxicities, treatment timing, and biomarker-guided patient selection. Collectively, these considerations support a biomarker-integrated and toxicity-aware development framework for TROP2-targeted therapy in SCLC.

In terms of structural design, emerging R&D trends are increasingly mechanism-informed, aiming to mitigate resistance arising from antigen heterogeneity, altered intracellular processing, efflux, and TOP1-pathway adaptation. Linker optimization that maintains plasma stability while enabling robust intracellular release may reduce vulnerability to impaired trafficking and lysosomal dysfunction; moreover, tuning linker cleavage chemistry and release kinetics can help preserve tumor-selective delivery while ensuring efficient payload liberation (117). The field has also emphasized cleavable-linker TOP1 payload platforms to enhance bystander activity in heterogeneous tumors, thereby addressing the dual challenges of moderate TROP2 expression and high intratumoral heterogeneity in SCLC (81). However, given the potential for transporter-mediated efflux and TOP1-associated resistance, next-generation payload design is increasingly focused on (I) TOP1 payload variants and linker-payload combinations that reduce efflux liability and (II) payload diversification beyond TOP1 inhibitors (e.g., microtubule inhibitors or other mechanism-based drugs) to reduce class-wide cross-resistance risks when sequencing ADCs (118,119). Concurrently, payload development continues to shift from very high DARs toward moderate DARs paired with more potent payloads and linkers offering better circulatory stability (126). Future efforts will involve the development of novel chemical bonds for linkers with greater resistance to physiological stressors as well as composite triggering mechanisms, aiming for efficient drug release within tumor cells while minimizing systemic exposure risks (127).

Given the predominance of TOP1 inhibitor-based payloads among leading TROP2-ADCs, SCLC-specific clinical implementation should emphasize practical considerations that directly inform monitoring and sequencing. First, toxicity management should be payload-aware: SN-38-based SG is primarily associated with hematologic and gastrointestinal toxicities (e.g., neutropenia and diarrhea), whereas DXd/exatecan payload platforms in lung cancer populations warrant heightened vigilance for ILD/pneumonitis and mucosal toxicities, which dictate screening, prompt evaluation of respiratory symptoms, and standardized interruption/discontinuation algorithms (92,95,111,128). Second, the anticipated role of TROP2-ADCs in SCLC is likely to evolve with confirmatory phase III readouts; positive results would be expected to influence later-line standards of care and subsequently reshape sequencing decisions. Third, because multiple agents in this class employ TOP1 payloads, cumulative TOP1 exposure and TOP1-pathway adaptation may contribute to cross-resistance, supporting careful sequencing (including consideration of non-TOP1 payload platforms where available) and rational trial designs that prospectively capture prior TOP1 exposure (119).

In terms of clinical application and combination strategies, as clinical research on ADCs in SCLC advances, the focus of evaluation has expanded beyond ORR and DOR to assess translation into survival benefits (PFS/OS), and the manageability of safety profiles. There is also an urgent need for the exploration of mechanisms underlying resistance to TROP2-ADCs in SCLC, improved drug efficacy, and expansion of strategies for combining ADCs with other agents, particularly immunotherapy. Immunotherapy can enhance the anti-tumor immunity induced by ADCs, improve the activities of immune effectors, and increase cell-mediated tumor recognition (66). Researchers are breaking new ground in NSCLC by analyzing the combinatory usage of TROP2-ADCs and immunotherapies. For example, co-administration of SG and pembrolizumab in the EVOKE-02 study achieved an impressive overall response rate of 56% and a DCR of 82%, while maintaining a safety profile consistent with what would be expected from either drug alone (79). In SCLC, current research is largely focused on SG monotherapy or combinations with non-immunotherapy agents. For example, a Phase I/II study (NCT04826341) evaluating the SG and berzosertib combination for second-line SCLC treatment seeks to determine its clinical feasibility, offering a potential pathway for optimizing subsequent-line treatment regimens.

Several limitations should be acknowledged. First, the clinical utility of TROP2 as a biomarker is constrained by the lack of standardized TROP2 IHC assays, including differences in antibody clones, staining platforms, scoring metrics (e.g., intensity scoring vs. H-score), and the absence of universally accepted cutoffs across studies, which complicates cross-trial comparisons and biomarker-driven enrichment strategies (129,130). Biomarker analyses in anti-TROP2 ADC programs have also suggested that TROP2 expression may not consistently correlate with clinical benefit across tumor types, underscoring the need for assay harmonization and prospective validation in SCLC. Second, although SLFN11 has been implicated as a marker of sensitivity to TOP1 inhibitors and other DNA-damaging agents in translational studies, its predictive value for TOP1-payload ADCs (e.g., SN-38- or DXd/exatecan-based ADCs) and its role in guiding sequencing in SCLC remain insufficiently defined (131,132). Future biomarker-integrated trials should therefore prospectively evaluate TROP2 assay standardization and explore whether SLFN11 (alone or in combination with TOP1-pathway alterations) can inform patient selection, prior TOP1 exposure considerations, and resistance monitoring in SCLC.

Looking ahead, greater attention should be directed toward integrative stratification strategies that incorporate TROP2 expression, DDR/SLFN11 status, and SCLC molecular subtypes, which may enable the transformation of effective yet unstable responses into more predictable and durable clinical benefit.

Conclusions

In summary, this review systematically outlines the current landscape of TROP2-targeting ADCs in the treatment of SCLC, integrating mechanistic insights, clinical evidence, and emerging translational perspectives. As a TAA that is expressed in a substantial proportion of SCLC cases and characterized by membrane localization and efficient internalization, TROP2 provides a biologically rational target for ADC-based drug delivery. Accumulating clinical evidence suggests that TROP2-directed ADCs, most notably SG, have demonstrated meaningful antitumor activity signals in previously treated ES-SCLC, leading to the U.S. FDA’s designation of breakthrough therapy and the initiation of registrational confirmatory trials. Nevertheless, therapeutic heterogeneity driven by variable TROP2 expression, treatment-related toxicities, and both primary and acquired resistance remain key challenge that may limit the durability and consistency of clinical benefit. Continued optimization of ADC structural design, refinement of patient selection and response monitoring strategies, and the development of mechanism-informed combination approaches may help define a more precise role for TROP2-ADCs in the later-line treatment of SCLC and ultimately contribute to incremental improvements in patient outcomes.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1467/prf

Funding: This work was supported by grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0521103), Tianjin Public Health Science and Technology Major Youth Project (No. 24ZXGQSY00090), Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion Open Funding Project (No. NCRCOP2023007), Tianjin Key Research Projects in Traditional Chinese Medicine (No. 2025011), Hebei Provincial Administration of Traditional Chinese Medicine Research Project (No. T2025083), Pilot Demonstration Project for the Inheritance and Innovative Development of Traditional Chinese Medicine in Nankai District, Tianjin (No. 20240204019), and First Teaching Hospital of Tianjin University of Traditional Chinese Medicine “Tuoxin Project” (Nos. y2023008 and y2023001).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1467/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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