ArticleFrontiers in immunology2026
Case Report: High TMB fails to predict immunotherapy response in
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Tumor mutational burden (TMB) is widely utilized as a predictive biomarker for response to immune checkpoint inhibitors (ICIs). However, a subset of hypermutated tumors exhibits primary resistance to immunotherapy, indicating that additional tumor-intrinsic mechanisms may override immunogenicity. Aberrant Hedgehog (Hh) signaling, frequently driven by Case presentation: We report a case of a 64-year-old male initially diagnosed with cutaneous squamous cell carcinoma (SCC). Comprehensive genomic profiling (CGP) of archival tumor tissue revealed an ultra-high TMB (95 muts/Mb) accompanied by a distinct ultraviolet (UV) mutational signature, with negative PD-L1 status. Based on the elevated TMB, dual immune checkpoint blockade was initiated; however, the patient did not achieve objective tumor regression. Reassessment of the genomic data, specifically the presence of a pathogenic truncating Results: Following the introduction of the targeted-immunotherapy combination, the patient achieved a durable and ongoing clinical response. Serial liquid biopsy analysis showed that the same PTCH1 alteration remained detectable during longitudinal assessment, supporting the biological relevance of Hedgehog pathway dysregulation in this case. Conclusion: This case highlights the limitations of relying solely on conventional biomarkers, such as TMB, even in the context of extreme hypermutation and UV-induced mutagenesis. CGP may be essential not only for therapeutic guidance but also diagnostic refinement. Our findings support the hypothesis that Hedgehog pathway inhibition may contribute to overcoming apparent resistance to immune checkpoint blockade in selected PTCH1-altered BCCs, supporting a biology-guided combinatorial approach in biomarker-discordant tumors with high TMB.
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