KRAS and STK11 co-mutations in resectable non-small cell lung cancer: enduring prognostic value and impaired immunotherapy response

Introduction

This commentary aims to contextualize the findings of Rosner et al. within the existing body of knowledge on Kirsten rat sarcoma virus (KRAS)/serine/threonine kinase 11 (STK11) co-mutations and neoadjuvant immunotherapy in early-stage non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have recently reshaped the treatment landscape of early-stage NSCLC in both the neoadjuvant and adjuvant settings (1,2). ICIs have introduced new opportunities for improving long-term outcomes, particularly through their ability to stimulate durable antitumor immune responses in selected patients. Nonetheless, a substantial proportion of patients ultimately experience disease recurrence, underscoring the need to identify additional predictive biomarkers that can guide treatment selection and optimize clinical benefit from ICIs even in the early stage setting (3).

Molecular biology of KRAS/STK11/KEAP1 co-mutations

Among the potential biomarkers in NSCLC, the KRAS gene has recently emerged as a pivotal oncogenic driver and a promising therapeutic target. The development of selective inhibitors of KRAS G12C, such as sotorasib and adagrasib, has yielded encouraging results in the metastatic setting (4,5). However, clinical experience in advanced disease has highlighted the substantial heterogeneity in responses to ICIs among KRAS-mutated (KRASmut) tumors, with distinct KRAS mutations exhibiting variable immune profiles and differential therapeutic vulnerabilities (6-8). Notably, the presence of co-occurring mutations, especially in the STK11 or KEAP1 genes, has been consistently associated with worse outcomes to ICIs based regimens (9,10). In particular, tumors harboring both KRAS and STK11 mutations (KRASmut/STK11mut), often referred to as the KL phenotype, are characterized by a distinct immunologically “cold” tumor microenvironment compared to KRASmut with no co-mutations. These tumors typically exhibit low levels of programmed death-ligand 1 (PD-L1) expression, minimal infiltration by effector lymphocytes, and an enrichment of immunosuppressive myeloid cells, collectively contributing to immune escape mechanisms and poor responsiveness to immunotherapy (11). The concomitant presence of KEAP1 mutations, may further exacerbate immune evasion by enhancing the tumor’s resistance to oxidative stress and impairing antigen presentation, thereby reinforcing an immunosuppressive tumor milieu (12). Recent retrospective analyses have demonstrated that NSCLC patients harboring KEAP1 mutations derive significantly less benefit from PD-(L)1 monotherapy, manifesting both shorter progression-free survival and reduced overall survival compared to KEAP1 wild-type cohorts (13). In addition, Zavitsanou et al. [2023] showed that KEAP1-mutant lung adenocarcinomas evade immune surveillance by hyperactivating the NRF2 pathway, which suppresses CD103⁺ dendritic-cell accumulation and downstream CD8⁺ T-cell effector functions, thereby driving resistance to PD-(L)1 blockade (14).

Clinical outcomes in resectable NSCLC

The cumulative evidence on the clinical impact of these co-mutations in the context of ICI-based treatments is summarized in Table 1, which highlights their prognostic relevance across multiple datasets in advance stage NSCLC.

Altogether, these complex and interdependent molecular features define a subgroup of NSCLC patients with particularly aggressive disease biology and limited treatment options. Their recognition in the metastatic setting has prompted growing interest in investigating whether similar mechanisms operate in earlier stages of the disease.

We read with great interest the study by Rosner et al., which stands among the first to integrate clinical and immunologic analyses of KRAS/STK11 co-mutations in patients with resectable NSCLC treated with neoadjuvant ICIs (15). The study included 61 patients enrolled in a phase I/II clinical trial investigating various neoadjuvant ICI-based strategies, including nivolumab alone, nivolumab plus ipilimumab, or nivolumab combined with platinum-doublet chemotherapy. Among the 52 patients with available baseline genomic sequencing, 21 (40.4%) harbored a KRAS mutation. Of these, 14 had co-occurring wild-type STK11 (KRASmut/STK11wt), while 7 harbored concurrent STK11 mutations (KRASmut/STK11mut). Pathologic response rates among KRAS-mutated patients were overall modest. Major pathological response (MPR) was achieved in 22% of cases, and complete pathological response (pCR) in only 6%. When assessing the KRASmut according to STK11 status, no significant differences were observed in pathologic response: MPR was 25% in KRASmut/STK11wt versus 17% in KRASmut/STK11mut (P=1.0). However, differences in recurrence outcomes were more pronounced. The median recurrence-free survival (mRFS) was significantly shorter in KRASmut/STK11mut patients (14.03 months) compared to those with KRASmut/STK11wt tumors (mRFS not reached), with a hazard ratio (HR) of 7.09 (P=0.027). Notably, this negative prognostic impact of STK11 mutations persisted when analyzing the entire cohort regardless of KRAS status (HR =3.3, P=0.031), though the vast majority of STK11-mutant tumors were also KRAS-mutant.

Interestingly, a trend toward higher pathologic responses was observed in KRAS wild-type patients compared to KRAS-mutant ones (MPR: 45% vs. 22%; pCR: 14% vs. 5%), but this did not translate into improved RFS [HR =1.0; 95% confidence interval (CI): 0.37–2.71; P=0.993]. Furthermore, within the KRAS-mutant group, recurrence risk did not differ significantly by type of KRAS mutation (G12C vs. non-G12C; HR =2.74; P=0.22) or by TP53 co-mutation status (HR =0.9; P=0.897).

Single-cell and immunologic mechanisms

To explain the apparent divergence between the impact of STK11 co-mutations on RFS and pathological response, the authors performed single-cell RNA and T-cell receptor sequencing on CD8⁺ tumor-infiltrating lymphocytes (TILs) from a subset of 13 patients treated with neoadjuvant ICIs: 6 with KRASmut/STK11mut tumors and 7 with KRASmut/STK11wt tumors. In KRASmut/STK11mut tumors, CD8⁺ TILs exhibited a transcriptional profile marked by terminal exhaustion and tissue residency. These cells expressed high levels of markers such as CD39 (ENTPD1) and ZNF683 (HOBIT), along with multiple inhibitory checkpoints including PD-1, TIM-3, and LAG-3, features suggestive of sustained antigen exposure coupled with diminished functional capacity, that raise the question whether these tumors may benefit from ICIs combination regimens in the early stage setting (NCT06918132). This phenotype may reflect a form of ineffective immune engagement that fails to confer durable tumor control despite the presence of cytotoxic markers. Conversely, in KRASmut/STK11wt tumors, CD8⁺ TILs displayed transcriptional features enriched for prostaglandin E2 (PGE2) signalling and reduced interleukin-2 (IL-2) signalling—molecular pathways that are classically associated with immunosuppression (16). Paradoxically, these signatures were observed in tumors with more favourable clinical outcomes, raising the possibility that, in this specific neoadjuvant context, they may reflect a distinct immune regulatory state rather than overt immune dysfunction, while the increased expression of genes such as NR4A3, PTGER2/4, and PDE7A further supports the presence of an alternative immunologic phenotype, although the functional implications of this profile remain to be fully elucidated. In addition, it is worth noting that single-cell analyses were performed on post-treatment resection specimens, and thus reflect the immune landscape shaped by neoadjuvant ICI exposure. As such, the observed transcriptional differences may represent not only intrinsic immune phenotypes, but also distinct patterns of treatment-induced immune modulation, potentially limiting their interpretability in terms of baseline immunobiology.

Integrating biology and clinical implications

Collectively, the findings presented by Rosner et al. (visual summary provided in Figure 1) provide an interesting exploratory view into the prognostic impact of STK11 co-mutations in resectable KRAS-mutant NSCLC treated with neoadjuvant ICIs. Although the study demonstrates a significantly shorter RFS in KRASmut/STK11mut tumors, this finding arises despite comparable pathologic response rates across the molecular subgroupsHowever, prior studies have reported a strong correlation between pCR or MPR and event-free survival in the broader NSCLC population (R²=0.82 and 0.81, respectively) (17), and the findings from this study cannot definitively challenge the validity of pathological response as a surrogate endpoint. Importantly, the directionality of pathological response consistently favored the STK11 wild-type group, even when applying alternative thresholds such as 50% residual viable tumor, suggesting that the absence of statistical significance may simply reflect limited power, rather than true biological equivalence. Furthermore, the transcriptomic analyses of CD8⁺ TILs were conducted on resection specimens collected after neoadjuvant ICI exposure and any attempt to define distinct immunologic trajectories from post-treatment snapshots in six to seven patients should be interpreted cautiously. Additional limitation to the study included heterogeneity in treatment regimens and schedules. Emerging evidence suggests that patients harboring STK11 co-mutations may derive particular benefit from combined programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition, which could partially overcome their otherwise immunosuppressive phenotype (18). Mechanistically, dual checkpoint blockade enhances CD4⁺ T-cell effector responses and reprograms the myeloid tumor microenvironment toward pro-inflammatory, tumoricidal phenotypes, counteracting the immunosuppressive milieu driven by STK11 loss (18). In this context, the inclusion of different ICI regimens, with small and uneven subgroup sizes, may have introduced a layer of interpretative uncertainty.

Figure 1 Visual summary of the clinical workflow and main translational insights, highlighting the key steps and findings across the study by Rosner et al. (A) Influence of KRASmut vs. KRASwt on outcomes to neoadjuvant ICI administration. (B) Influence of KRASmut/STK11mut vs. KRASmut/STK11wt on outcomes to neoadjuvant ICI administration. CD8⁺ TIL, CD8⁺ tumor-infiltrating lymphocyte; ICIs, immune checkpoint inhibitors; IL-2, interleukin-2; KRAS, Kirsten rat sarcoma viral oncogene homolog; MPR, major pathological response; mRFS, median recurrence-free survival; mut, mutation; NSCLC, non-small cell lung cancer; PGE2, prostaglandin E2; pCR, complete pathological response; RFS, recurrence-free survival; STK11, serine/threonine kinase 11; wt, wild type.

Although STK11, and similarly KEAP1, are currently regarded as primarily prognostic markers rather than predictive of response to ICIs (19), the findings from this study reinforce the importance of further investigating their functional role in shaping the antitumor immune response. In the metastatic setting, a growing body of evidence has consistently associated co-mutations in STK11 and KEAP1 with poor clinical outcomes, including reduced responsiveness. Nonetheless, the complexity of co-mutational patterns must be acknowledged, as emerging evidence suggests that STK11-mutant tumors harboring TP53 co-mutations may display a more inflamed microenvironment and distinct responses to ICIs (20). These molecular alterations have been shown to promote an immune-evasive tumor microenvironment, characterized by low PD-L1 expression, low tumor mutational burden, reduced T-cell infiltration, and increased presence of immunosuppressive myeloid cells (10).

Future directions and clinical implications

A deeper understanding of the functional implications of STK11 and KEAP1 co-mutations in early-stage disease could help refine risk stratification, guide the development of novel therapeutic strategies, and optimize patient selection for immunotherapy. Reflecting this need, dedicated clinical trials are currently investigating targeted strategies in this molecularly characterized population (21).

Clinically, this study reinforces the role of KRAS/STK11 co-mutations as a negative prognostic factor even in resectable NSCLC, suggesting that their identification may support intensified perioperative approaches and tailored post-operative surveillance in high-risk patients. However, the study by Rosner et al., while ambitious in scope, is limited by its exploratory nature, small sample size, and heterogeneity of treatment regimens, tumor stage and PDL1 expression. Perhaps its most compelling message is that biomarkers such as STK11 and KEAP1, traditionally considered static and prognostic, may have context-dependent roles that vary with disease stage, treatment modality, and timing of assessment. In the neoadjuvant setting, where both tumor and immune compartments are dynamically altered, their behavior and impact may diverge from what has been observed in advanced disease.

These results support the incorporation of KRAS/STK11 co-mutation status as a stratification criterion in ongoing and future perioperative ICI trials, enabling focused assessment of intensified or combination regimens for high-risk subgroups. Moreover, implementing tissue- and liquid-biopsy assays to detect these co-mutations may facilitate real-time, biomarker-driven patient selection and response monitoring in early-stage NSCLC.

Conclusions

In conclusion, our findings highlight STK11 and related co-mutations as dynamic, context-sensitive markers whose prognostic and predictive roles evolve from metastatic to early-stage NSCLC. Embracing this nuance will be essential for building integrated, stage-specific biomarker models that guide truly personalized immunotherapy strategies for each patient.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-463/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-2025-463/coif). F.F. receives speaker fees from Roche. A.R.N. receives honoraria from NGM Biopharmaceuticals; consulting fees from Foundation Medicine, Astellas Pharma, and Natera; research funding to his institution from Loxo/Lilly, Surface Oncology, ADC Therapeutics, IgM Biosciences, EMD Serono, Aravive, NiKang Therapeutics, Revolution Medicines, Jazz Pharmaceuticals, Immunocore, Phanes Therapeutics, Kymera, Inspirna, and AbbVie; and support for travel, accommodations, and expenses from Foundation Medicine, Binaytara Foundation, Society for Immunotherapy of Cancer, ASCO, American Society for Radiation Oncology, IDEOlogy Health, and Jazz Pharmaceuticals. B.R. serves as a consultant/advisory board member for AMGEN, Regeneron, AstraZeneca, and Capvision; and receives speaker fees from AstraZeneca; honoraria from Targeted Oncology and the Society for Immunotherapy of Cancer; and travel support from Bristol-Myers Squibb and Genentech. A.C. receives consulting fees from Bristol-Myers Squibb, AstraZeneca, MSD Oncology, Regeneron, Amgen, Daiichi Sankyo/AstraZeneca, Roche, Access Infinity, Ardelis Health, IQVIA, Alpha Sight, Capvision, techspert.io, Atheneum, Alira Health, Tegus, and Johnson & Johnson/Janssen; honoraria from AstraZeneca, MSD Oncology, Sanofi/Regeneron, Roche, and Johnson & Johnson/Janssen; research funding (to institution) from the International Association for the Study of Lung Cancer; travel support (travel, accommodations, expenses) from Roche and MSD Oncology; and has other personal relationships with MSD Oncology, Bristol-Myers Squibb, and GSK. The other 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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