MLH1 mismatch repair deficiency predicts exceptional response to immune checkpoint inhibition in clear-cell renal cell carcinoma

The study by Dawidek et al. provides a concise yet striking contribution to the evolving landscape of biomarker-driven therapy in clear-cell renal cell carcinoma (ccRCC). In a disease historically devoid of reliable predictive markers, the identification of MLH1 mismatch repair (MMR) deficiency as a robust predictor of exceptional response to immune checkpoint inhibition (ICI) marks a potential paradigm shift. Using genomic and immunohistochemical data from large, well-characterised cohorts (including validation in the CheckMate-214 and JAVELIN Renal 101 trials) the authors demonstrate that although MLH1 loss-of-function events are rare (approximately 2–3% of cases), they are consistently associated with deep and durable responses to PD-1/PD-L1-based therapies, often meeting criteria for “exceptional responders.”

The novelty of these findings lies not only in the molecular specificity—focusing on MLH1 rather than the broader, and previously inconclusive, MMR gene set—but also in the translational feasibility. The authors demonstrate that MLH1 deficiency can be detected using clinically available sequencing platforms, a crucial step toward the routine clinical application. The biological rationale is compelling: MLH1 loss enhances neoantigen generation, enriching for immunogenic mutations that may drive durable immune responses, even in the typically low tumour mutational burden environment of ccRCC. Interestingly, the study observes MMR-deficient mutational signatures even in microsatellite-stable tumours, suggesting that classical MSI testing may underestimate the prevalence of this phenotype.

From a clinical perspective, the implications are substantial. Current first-line standards for metastatic ccRCC rely on ICI-based combinations, but treatment selection remains empirical. Biomarker-informed strategies could refine these decisions, especially in distinguishing patients most likely to derive sustained benefit from dual immune blockade versus ICI-VEGF combinations. The observation that MLH1-deficient tumours responded poorly to VEGF monotherapy yet exceptionally well to immunotherapy underscores the need for molecular stratification in trial design and therapeutic sequencing. Moreover, as adjuvant immunotherapy with pembrolizumab gains traction following KEYNOTE-564, MLH1 status might serve as a valuable marker to optimise patient selection and spare low-likelihood responders’ unnecessary toxicity.

Methodologically, the study’s integration of multi-omic profiling, immunohistochemistry, and external validation across phase III datasets elevates its credibility. However, several challenges remain before clinical implementation. The rarity of MLH1 deficiency in ccRCC raises questions about cost-effectiveness for universal screening, and the potential confounding effect of antigen-presentation defects suggests that MLH1 loss alone may not guarantee responsiveness. Furthermore, the discordance between MLH1 genomic loss and RNA expression observed in the JAVELIN cohort points to a complex regulatory landscape that may involve epigenetic silencing, an avenue that warrants further exploration through methylation and transcriptomic assays.

Overall, this work represents one of the most significant advances in precision immuno-oncology for renal cancer in recent years. By pinpointing MLH1 deficiency as a molecular determinant of ICI sensitivity, Dawidek et al. bridge a long-standing gap between genomic insight and therapeutic decision-making in ccRCC. If validated prospectively, incorporating MLH1 testing into standard diagnostic panels could finally bring us in a biomarker-guided era for renal cancer immunotherapy, an achievement that has remained elusive until now, despite a decade of checkpoint inhibitor innovation.