Role and clinical significance of VISTA (PD-1H) and PVR (CD155) expression in non-small cell lung carcinoma: a systematic review

Introduction

Lung carcinoma remains the most common cancer type and the leading cause of cancer-related mortality worldwide in both sexes combined (1). The predominant histological form, accounting for approximately 85% of cases, is non-small cell lung carcinoma (NSCLC) (2). NSCLC is a heterogeneous group comprising several major subtypes, most notably squamous cell carcinoma (SCC), adenocarcinoma (AD), and large cell carcinoma (LCC) (3). Although cigarette smoking is the major etiologic factor, its association varies by subtype and is stronger for SCC than for AD, which is more frequently diagnosed in never-smokers (4). Despite advances in systemic therapy, outcomes remain poor (e.g., ~15% 5-year survival in stage III disease) (5). While molecular targets such as EGFR, ALK, ROS1, K-Ras, and PD-L1 have entered clinical practice, therapeutic benefit is often limited by tumour resistance (4). Therefore, novel immune-related targets that can overcome resistance mechanisms in NSCLC remain an unmet need.

V-domain immunoglobulin suppressor of T-cell activation (VISTA, also known as PD-1H) is a transmembrane B7-family protein consisting of an immunoglobulin IgV domain and a stalk region that links to the transmembrane domain. It is implicated in immune regulation, including maintenance of T-cell quiescence, modulation of natural killer (NK) cell activity, regulation of antigen presentation by antigen-presenting cells (APCs), and support of regulatory T cells and myeloid-derived suppressor cells (MDSCs). VISTA is increasingly recognised as a multifunctional immune checkpoint protein. In addition to its role as a receptor for VSIG3 and galectin-9, VISTA can also function as a ligand, interacting with PSGL-1 and PD-1. Furthermore, recent studies suggest that VISTA may exert intracellular functions, indicating a more complex regulatory role beyond classical ligand-receptor interactions. These findings highlight the pleiotropic nature of VISTA in immune regulation (6-10). VISTA expression has been reported in multiple malignancies, including renal cell carcinoma, pancreatic AD, sarcomas, and gliomas (11).

CD155 (poliovirus receptor, PVR) is a nectin-like family member, that shares structural features with nectins, including an extracellular region composed of three immunoglobulin-like domains. It is involved in adhesion, migration, proliferation, and immune regulation. By engaging activating (DNAM-1) and inhibitory (TIGIT, CD96) receptors, CD155 can modulate immune-cell function and has been implicated in tumour immune evasion and progression across diverse cancers (12).

Representative histopathological images of two major NSCLC subtypes are shown in Figure 1A-1D.

Figure 1 Representative histopathological features of major NSCLC subtypes. (A,B) Lung adenocarcinoma. (C,D) Squamous cell carcinoma. H&E staining; original magnification ×20 (A,C) and ×100 (B,D). Images were obtained from anonymised archival material of the Department of Pathomorphology of Medical University of Silesia in Katowice and are presented for illustrative purposes. H&E, hematoxylin and eosin; NSCLC, non-small cell lung cancer.

Therefore, this systematic review aims to integrate and critically synthesise the current evidence on VISTA and CD155 in NSCLC, framing them as two largely distinct, potentially convergent immune-regulatory axes that may contribute to tumour immune evasion in an emerging, still underexplored area of NSCLC immunobiology. We present this article in accordance with the PRISMA reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0402/rc) (13).

Methods

The aim of this systematic review was to evaluate the expression patterns, molecular functions, and clinical significance of CD155 (PVR) and VISTA (PD-1H) in NSCLC. A literature search was performed in PubMed, Scopus, Embase, and Web of Science and completed in September 2025; database-specific search strategies are provided in Appendix 1. The review was registered in PROSPERO (CRD420251171414) (14).

After merging records and duplicate removal, a total of 115 records were identified. Two reviewers independently screened titles/abstracts, with discrepancies resolved by consensus. Sixty-one articles underwent full-text review; 50 studies met inclusion criteria (21 VISTA; 29 CD155). An updated search was conducted on 1 May 2026 using additional synonyms for VISTA (VSIR, B7-H5, DD1a, Dies1) and CD155 (Necl-5, TAGE-4) across PubMed, Scopus, and Embase. This search identified one additional eligible study. Therefore, a total of 51 studies (22 VISTA; 29 CD155) were included in the final analysis. Data extraction was performed independently by two investigators, with discrepancies resolved by consensus. Inclusion and exclusion criteria are summarised in Table S1.

Risk of bias was assessed independently by two reviewers using the Newcastle-Ottawa Scale (NOS) for studies involving human samples and SYRCLE’s risk of bias tool for animal studies (15,16) (tables available at https://cdn.amegroups.cn/static/public/tlcr-2026-0402-1.xlsx). The certainty of evidence for major outcome domains was assessed qualitatively using GRADE domains as a structured framework (17). Each outcome domain was evaluated with regard to study design, risk of bias, inconsistency, indirectness, imprecision, and potential publication bias.

Extracted data were organised into separate spreadsheets for each marker and included NSCLC subtype or experimental model, expression patterns, downstream molecular effects, associations with the immune microenvironment, correlations with other biomarkers, and prognostic outcomes. Studies were grouped into thematic categories (expression, immune regulation, PD-L1 association, functionality, and prognostic relevance). An artificial intelligence-based language model (ChatGPT, OpenAI) was used to assist with language editing of the manuscript.

Due to substantial heterogeneity across study designs, NSCLC subtypes, and methodologies, no meta-analysis was performed. Instead, a structured narrative synthesis supported by summary tables was conducted. The PRISMA flow diagram is shown in Figure 2.

Figure 2 PRISMA 2020 flow diagram summarizing the selection process.

Narrative synthesis was conducted in accordance with guidance for synthesis without meta-analysis (SWiM) (18). Studies were grouped by biomarker (VISTA vs. CD155) and further categorised by outcome domain, including expression patterns, immunological role, and prognostic or predictive significance. Within each category, findings were summarised descriptively, and the direction of effect was determined based on whether studies reported positive, negative, or no association with the outcome of interest.

In cases of conflicting results, greater emphasis was placed on studies with larger sample sizes, more rigorous methodology, and those conducted in clinical human cohorts. Preclinical (in vitro and in vivo) studies were synthesised separately and used primarily to support mechanistic interpretation rather than clinical conclusions. No quantitative synthesis was performed due to substantial heterogeneity in study design, patient populations, detection methods, and outcome definitions.

Results

A total of 115 records were identified after deduplication. Screening of abstracts and subsequent full-text evaluation resulted in 51 eligible studies. Among them, 22 focused on VISTA (PD-1H) and 29 on PVR (CD155) role in NSCLC.

VISTA expression in NSCLC

Among the twenty-two studies addressing VISTA in NSCLC, twenty evaluated VISTA expression in tumour samples. VISTA was detected across NSCLC tissues, including neuroendocrine tumours (19-31). In four studies, VISTA positivity was reported in a very high proportion of samples (85–100%) (24,27,28,30). Multiple studies consistently indicated predominant VISTA expression within the tumour stroma (19,20,24,28,29), with immune-cell localisation on CD3⁺ T cells (including CD8⁺ tumour-infiltrating lymphocytes), B regulatory cells (Breg), CD4⁺ lymphocytes, and CD68⁺ macrophages (21,22,24,25,28,29). One microarray-based analysis reported downregulation of VSIR (encoding VISTA) in stage IIIA NSCLC, while another study also observed reduced expression, with a negative correlation to EGFR expression (32,33).

VISTA was also detected in brain metastases of lung AD (BM-AD), localising to tumour cells as well as CD3⁺ T cells and microglia (34,35). Although expression was lower in metastases than in matched primary tumours, it remained detectable (35).

Potential regulatory influences were reported in preclinical studies: METTL3 and YTHDF1 were implicated in VISTA regulation (36), and inhibition of iASPP in A549 cells was associated with activation of a VSIR enhancer (37). Clinical context may further modulate expression; in HIV-positive NSCLC, higher levels of immunoregulatory markers, including VISTA, were observed, particularly on tumour-associated macrophages (TAMs) (22).

Two studies examined associations with other checkpoints. VISTA positively correlated with PD-L1 on tumour-associated lymphocytes and macrophages (24), whereas no correlation was observed between VISTA on tumour cells and PD-L1 on lymphocytes (26). In neuroendocrine lung tumours, VISTA correlated with OX40L and TIM-3 on tumour cells (31).

Several studies highlighted heterogeneity: VISTA on CD68⁺ macrophages was higher in AD and SCC than in LCC (21); microarray analyses showed marked regional variability, supporting the need for spatially resolved approaches (38); and stromal VISTA tended to be lower in EGFR-mutant tumours (24). Overall, VISTA is consistently detectable in NSCLC, predominantly within stromal/immune compartments, with substantial context- and tumour-dependent variability.

VISTA influence on NSCLC immunology

VISTA expression has been detected on multiple immune-cell populations infiltrating NSCLC, including CD3⁺ and CD8⁺ T cells, CD4⁺ lymphocytes, CD68⁺ macrophages, and Breg cells (21-25,28,29,31). In BM-AD, VISTA was likewise observed on tumour cells, CD3⁺ lymphocytes, and microglia infiltrating metastatic lesions (34).

Several studies suggest that VISTA is associated with an immunosuppressive tumour microenvironment. CD4⁺VISTA⁺ T cells were linked to reduced Th1 (IFN-γ, IL-2), Th2 (IL-4), Treg-associated (IL-10) and Th17 (IL-17) cytokines in NSCLC tissue compared with adjacent normal lung (28). VISTA expression on Breg cells-an IL-10 and TGF-β-producing immunoregulatory population-was also reported (25). Additional associations included a negative correlation with dense collagen barriers (21) and altered levels of regulatory T cells within tumour tissue (26).

Functional data support an immunomodulatory role of VISTA. In vitro and in vivo VISTA blockade enhanced CD8⁺ T-cell activation, increased cytotoxicity against NSCLC cells, and promoted differentiation toward a pro-inflammatory Th1 phenotype (39). Conversely, VISTA overexpression in A549 and H1299 cells co-cultured with PBMC enhanced CD8⁺ T-cell cytotoxicity in another setting (36), highlighting context-dependent effects. VISTA has also been reported to positively associate with PD-L1 expression on tumour-associated immune cells (24), whereas no correlation was found between VISTA on tumour cells and PD-L1 on lymphocytes (26). One study reported an association between EGFR-mediated immune evasion and the VISTA pathway (33).

Overall, current evidence supports a role for VISTA in shaping the NSCLC immune microenvironment, predominantly toward immunosuppression, although experimental findings indicate context dependence, warranting further mechanistic and translational studies.

Vista association with prognosis

Eight studies evaluated the association between VISTA expression and clinical outcomes in NSCLC, yielding heterogeneous findings. Three studies reported that high VISTA expression was associated with poorer survival, including shorter overall survival (OS), and one identified VISTA as an independent prognostic factor in multivariate analysis (19,21,28). The presence of VISTA⁺ Breg cells was also linked to a higher risk of tumour recurrence (25). In contrast, two studies, including one on neuroendocrine tumours, found no significant association with prognosis (23,31), whereas one study suggested improved OS with higher VISTA expression (24). Additionally, decreased VISTA expression on Th1 lymphocytes correlated with poorer treatment response (40). Overall, given the limited evidence base and substantial heterogeneity, VISTA cannot currently be considered a reliable prognostic biomarker in NSCLC.

CD155 expression on NSCLC

Among the twenty-nine studies addressing CD155 (PVR) in NSCLC, twenty-seven evaluated CD155 expression in tumour samples. CD155 was detected across multiple NSCLC contexts (including AD, SCC, stage I AD, advanced-stage tumours, and NSCLC cell lines) and was also reported on M2-like macrophages infiltrating bone marrow metastases (41-58). In most studies, CD155 localised predominantly to the tumour-cell membrane (41,46,50), and expression was higher in NSCLC tissue than in normal lung (41,49). CD155 was also identified on extracellular vesicles released by NSCLC cells (41).

Substantial heterogeneity was reported between subtypes and within tumours. Higher expression was described in papillary and solid AD, and primary tumours showed stronger staining than matched metastases (48,55-57). CD155 was not universally expressed, with reported prevalence ranging from approximately 40% to 97% across cohorts (42,43,45,52-54). Among CD155-positive cases, expression levels varied widely (high vs. low expressers) (43,49,54), and intratumoral heterogeneity was observed, with high-expression regions adjacent to minimally stained areas (50).

Several regulators of CD155 were identified in preclinical studies. NECTIN4 stabilised CD155 and protected it from degradation (59), whereas multiple microRNAs (miR-346, miR-328-3p, miR-326, miR-330-5p) suppressed CD155 at mRNA and protein levels (60). The integrated stress response (ISR) upregulated CD155 in NSCLC cell lines (61) and silencing of SPOP in A549 cells reduced CD155 expression (62). Dasatinib exposure—or Src silencing—reduced CD155 in cisplatin-resistant NSCLC lines (H460R and A549R) (63). Cytokine signalling also influenced CD155; IL-6 increased CD155 at both mRNA and protein levels via the JAK-STAT pathway (55).

Finally, cytostatic agents (cisplatin, paclitaxel, carboplatin, gemcitabine, vinorelbine) were reported to modulate CD155 expression in a cell-line-dependent manner; for example, gemcitabine altered CD155 in A549 but not in H460 or H1703 (64,65). In clinical samples, one study reported a non-significant trend toward decreased CD155 expression after chemoradiotherapy (66).

CD155 association with PD-L1

The association between CD155 and PD-L1 expression in NSCLC was evaluated in fourteen studies. Nine reported a positive correlation or co-expression in human NSCLC samples (42,45,48,52,53,57,58,61,67). Contradictory results were uncommon: one study described a weak, non-significant negative correlation in the lobular growth pattern (50), and another found no association (47). This variability may reflect that concurrent upregulation occurs only in a subset of tumours (58) and may differ across histological growth patterns, with the highest levels reported in solid-type tumours (48,57).

Mechanistic links have been suggested. Carboplatin increased PD-L1 in NSCLC cell lines in a CD155-dependent manner, as CD155 silencing attenuated PD-L1 induction; this effect involved EGFR, PI3K/AKT, and ERK signalling, since pathway inhibition reduced upregulation of both markers (67). Activation of the ISR increased CD155 and PD-L1 at the translational (but not mRNA) level (61), and miR-326 was downregulated in tumours with high co-expression of CD155 and PD-L1 (60).

Seven studies evaluated prognostic implications of CD155/PD-L1 co-expression (43,45,47,52,53,57,58). Concurrent high expression was consistently associated with poorer outcomes, including reduced OS and progression-free survival (PFS) (43,45,52,53,57,58). In several reports, CD155 alone showed limited prognostic value but became informative when assessed together with PD-L1 (52,57). High CD155 expression was also linked to reduced efficacy of PD-1/PD-L1-axis immunotherapy, most directly shown for anti-PD-1 treatment (45,47,59).

Overall, available evidence supports that a subset of NSCLC tumours co-expresses CD155 and PD-L1, which is associated with adverse prognosis and impaired response to PD-1/PD-L1-targeted therapy.

CD155 influence on immunology

Fifteen studies addressed the role of CD155 in shaping the NSCLC immune microenvironment. Overall, most reports support a predominantly immunosuppressive function, although some findings are context-dependent. The most consistent evidence concerns T lymphocytes: five studies reported that CD155 suppresses T-cell responses and effector functions (55,59-61,67), whereas one study associated high CD155 with increased infiltration of CD3⁺, CD4⁺, and CD8⁺ tumour-infiltrating lymphocytes (53). Data on NK-cell cytotoxicity were inconsistent, with reports of both enhanced and inhibited NK-cell activity at higher CD155 expression (64,68).

Additional support for an immunosuppressive role includes CD155 expression on M2-like macrophages in bone marrow metastases (44) and experimental data showing that Src inhibition, accompanied by reduced CD155, decreased M2 polarisation and lowered MIF expression (63). CD155 also correlated with other inhibitory molecules, including LSECtin, PD-L1 and CTLA-4, suggesting coordinated co-inhibitory signalling within the tumour microenvironment (46,49,53,58). Mechanistically, ISR activation in CMT167 models induced both CD155 and PD-L1 expression (61), and IL-6 increased CD155 in NSCLC cell lines; concordantly, positive correlations between IL-6 and CD155 were observed in tumour tissue and serum from NSCLC patients (55).

Translationally, a preclinical A549 xenograft model suggested CD155 as a CAR-T target (69). High CD155 expression, often co-existing with PD-L1, has been linked to reduced responsiveness to PD-1/PD-L1-axis immunotherapy (56,59,61). Combination strategies, including PD-1 blockade with TIGIT inhibition or modulation of the ISR pathway, showed enhanced antitumour efficacy in preclinical settings (56,59,61). Overall, current evidence supports CD155 as a contributor to an immunosuppressive NSCLC microenvironment, while allowing for context-dependent effects.

CD155 influence on prognosis

Sixteen studies examined prognosis and treatment outcomes in relation to CD155. Overall, most evidence supports an adverse prognostic association: ten studies reported that high CD155 expression correlated with poorer outcomes, most commonly reduced OS and PFS (43,45,47,49,51-54,58,63). Two studies found no association with survival (57,66), suggesting context dependence. For example, CD155 was associated with reduced OS and PFS in EGFR-wild-type NSCLC but not in EGFR-mutated tumours (54), and prognostic effects varied by stage (present in stage I–III AD but not when restricted to stage II–III) (52).

Associations were more consistent when CD155 was assessed together with PD-L1. Co-expression repeatedly predicted worse prognosis across cohorts (43,45,47,52,53,57,58), and in some analyses provided stronger stratification than CD155 alone (52). Notably, even in a study where CD155 alone lacked prognostic value, the CD155/PD-L1 co-expression pattern significantly stratified survival (57).

Beyond survival, high CD155 was linked to poorer treatment response, including reduced efficacy of anti-PD-1 therapy (43,45,47,56,59). CD155 also correlated with aggressive disease features, including advanced stage (41,49,58), vascular invasion, and pleural infiltration (including in co-expression analyses with PD-L1) (52-54). Bioinformatic analyses associated high CD155 with larger tumour volume and reduced immune infiltration (41,56).

Preclinical studies provide mechanistic support for targeting CD155, including potent activity of CD155-directed CAR-T cells in A549 xenograft models (69) and superior efficacy with minimal toxicity of doxorubicin-loaded liposomes conjugated to a CD155-specific nanobody in patient-derived NSCLC organoids in vivo (51); however, these findings do not directly translate into clinical applicability. Selected numerical effect estimates (hazard ratios, confidence intervals, and P values) for statistically significant associations between CD155 expression and clinical outcomes are summarized in Table S2.

In summary, CD155 is most often associated with unfavourable prognosis in NSCLC, although effects may vary across molecular and clinical subgroups. Co-expression of CD155 and PD-L1 appears to provide more consistent prognostic stratification than CD155 alone. Key findings on expression, immune effects, and clinical associations of VISTA and CD155 are summarised in Table 1.

Methodological heterogeneity in CD155 and VISTA measurement

Substantial methodological heterogeneity across studies likely contributed to variability in reported clinicopathological and prognostic associations for CD155 and VISTA. Differences were evident not only between human, animal, and in vitro studies but also among human cohorts.

In human NSCLC, immunohistochemistry (IHC) predominated, yet antibodies, scoring systems, cut-offs, and stratification varied widely. CD155 was assessed using TPS-based or multi-tier percentage scales and/or intensity-weighted systems, with inconsistent thresholds for “high/positive” expression (e.g., ≥5%, ≥10%, or ≥50%). Cut-offs were defined by receiver operating characteristic (ROC)-based optimisation or predefined/arbitrary criteria. For VISTA, IHC typically used intensity scores (0–3) or H-scores, whereas a minority of studies applied alternative methods such as flow cytometry, particularly for immune-cell subsets.

Survival endpoints were relatively consistent (mainly OS and PFS with Kaplan-Meier analyses), but comparability was limited by heterogeneous cohorts (mixed NSCLC vs. selected subtypes/stages). Experimental studies additionally used Western blotting, quantitative polymerase chain reaction (qPCR), and functional assays, which are informative mechanistically but not directly comparable with IHC-based clinical assessments.

Overall, non-standardised assessment—especially scoring, cut-offs, and stratification—remains a major source of heterogeneity and may partly explain inconsistent prognostic findings, particularly for VISTA. Harmonised protocols are needed to support robust comparisons and clinical translation.

Certainty of evidence assessment

The certainty of evidence was assessed for four major outcome domains: VISTA expression/localization, VISTA prognostic relevance, CD155 prognostic relevance, and CD155/PD-L1 co-expression and immunotherapy resistance. The certainty of evidence for VISTA prognostic relevance was judged as very low, mainly due to inconsistency across studies. The remaining outcomes were assessed as low certainty. Detailed assessments for each outcome are presented in Table S3.

Potential reporting bias and small-study effects were considered qualitatively due to the predominance of retrospective single-centre studies and the absence of prospective validation studies.

Discussion

Despite advances in systemic therapy, resistance and immune escape remain major barriers in NSCLC, highlighting the need for additional immune targets. VISTA (PD-1H) and CD155 (PVR) have emerged as candidate modulators of anti-tumour immunity.

Both molecules are expressed in NSCLC but show distinct compartmentalisation. VISTA is predominantly detected in stromal and tumour-associated immune-cell compartments, whereas CD155 is mainly tumour-cell associated, higher in malignant than adjacent non-tumour tissue, and heterogeneous across and within tumours. This variability suggests CD155 may mark biologically distinct subgroups, warranting standardised assessment and prospective validation.

Overall, available data support immunosuppressive functions for both pathways, although evidence is stronger for CD155. VISTA has been linked to altered cytokine profiles and immunoregulatory populations (including regulatory B cells) but remains understudied and heterogeneous. In contrast, CD155 is more consistently associated with impaired T-cell function and coordinated co-inhibitory signalling, most reproducibly with PD-L1. Although VISTA and CD155 operate through distinct molecular pathways, both contribute to immune evasion within the tumour microenvironment. Notably, both axes are functionally linked to PD-1/PD-L1 signalling and may act in parallel to suppress T-cell activity. This suggests that co-expression or co-targeting of these pathways could have synergistic implications for immune modulation, although direct mechanistic interactions remain to be fully elucidated.

Clinically, evidence is currently insufficient to support VISTA as a prognostic biomarker. CD155 more often correlates with poorer outcomes (including reduced OS and PFS), with effects that appear context-dependent (e.g., molecular background or stage). Prognostic stratification is most consistent when CD155 is assessed together with PD-L1, suggesting co-expression may outperform either marker alone.

CD155-targeted strategies are promising in preclinical models (e.g., CAR-T and antibody/nanobody-based approaches), but translation will require robust in vivo validation and biomarker-driven patient selection. The clinical relevance of CD155 should also be interpreted in the context of the CD155/TIGIT axis, which represents an emerging immune checkpoint pathway involved in tumour immune evasion. CD155 interacts with TIGIT on T cells and NK cells, leading to inhibitory signalling and impaired anti-tumour immune responses (70). Early clinical data from the CITYSCAPE phase II trial suggested that combining anti-TIGIT therapy with PD-L1 blockade may improve outcomes in patients with NSCLC, particularly in PD-L1-high tumours (71). However, these findings were not confirmed in the subsequent phase III SKYSCRAPER-01 trial, which failed to demonstrate a significant clinical benefit (72). Ongoing clinical programmes, including those evaluating domvanalimab, continue to explore the therapeutic potential of TIGIT inhibition (73). These mixed results highlight the complexity of the CD155/TIGIT axis and suggest that CD155 expression alone may be insufficient as a predictive biomarker, reinforcing the need for better patient stratification and combinatorial biomarker approaches.

Study limitations

Evidence is limited by heterogeneity of NSCLC subtypes and patient cohorts, predominance of retrospective designs, and non-standardised assays (antibodies, scoring systems, cut-offs), which preclude meta-analysis and may explain inconsistent prognostic findings. Functional and in vivo data remain relatively scarce; therefore, mechanistic and therapeutic conclusions—particularly for VISTA—are preliminary.

Recommendation for future studies

Current research on both CD155 and VISTA in NSCLC faces several challenges. One major issue is the biological heterogeneity of NSCLC, which represents a heterogeneous group of malignancies that are often analysed as a single entity. In addition, many studies do not account for clinically significant molecular alterations, such as EGFR mutations, which may influence tumour biology and clinical behaviour. Therefore, future studies may benefit from characterising the distinct expression patterns and clinicopathological significance of CD155 and VISTA across different histological and molecular subtypes of NSCLC.

Another important limitation is the methodological heterogeneity between studies. To improve reproducibility and clinical interpretability, cut-off values should preferably be predefined or externally validated rather than derived solely from data-driven approaches such as ROC optimisation, which may introduce bias. Furthermore, future studies may benefit from establishing minimum reporting datasets including antibody clone, scoring system, cut-off definition, clinical endpoint, and direction of association to facilitate comparison across studies.

Certainty assessment and bias reporting

A qualitative GRADE-based assessment demonstrated that the certainty of evidence across most outcome domains was low, mainly due to retrospective and observational study design, inconsistency in results and the possibility of publication bias. The certainty of evidence for VISTA prognostic relevance was assessed as very low because of substantial inconsistency between studies and conflicting prognostic findings across clinical subgroups.

Risk of bias in studies involving human samples was generally low according to the NOS, whereas preclinical animal studies assessed with the SYRCLE tool most commonly demonstrated moderate risk of bias. Nevertheless, the predominance of retrospective single-centre studies may increase the risk of selective reporting and small-study effects.

Conclusions

This systematic review summarizes current evidence on the expression, biological role, and clinical significance of VISTA (PD-1H) and CD155 (PVR) in NSCLC. The available studies indicate that both molecules are expressed in NSCLC and appear to contribute to shaping the tumour immune microenvironment. However, the clinical significance of VISTA remains insufficiently defined due to limited and heterogeneous data. In contrast, several studies suggest that CD155 expression may be associated with adverse prognosis in selected patient groups. Nevertheless, the considerable heterogeneity in study design, detection methods, and cut-off definitions limits direct comparison between studies. Further well-standardized investigations are required to clarify the prognostic and potential therapeutic relevance of VISTA and CD155 in NSCLC.

Acknowledgments

The authors used the artificial intelligence–based language model ChatGPT (OpenAI) to assist with language editing and improvement of the manuscript’s linguistic style. All scientific content and interpretations were reviewed and approved by the authors.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0402/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0402/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0402/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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