{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:05:38Z","timestamp":1790057138708,"version":"4.0.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>PTCH1<\/jats:italic>\n                      inactivation in basal cell carcinoma (BCC), has been implicated in immune exclusion and suppression of antitumor immunity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>PTCH1<\/jats:italic>\n                      (Y977fs*16) alteration alongside the UV signature, raised a strong suspicion of basal cell carcinoma with squamous differentiation, prompting a diagnostic revision. Given the established role of PTCH1 loss in constitutive Hedgehog (Hh) pathway activation and immune exclusion, we considered aberrant Hedgehog signaling to be a biologically plausible contributor to the limited objective response observed during initial immune checkpoint blockade. Consequently, a rational combinatorial strategy utilizing vismodegib (an Hh pathway inhibitor) and pembrolizumab was initiated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1814345","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:40:21Z","timestamp":1790055621000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: High TMB fails to predict immunotherapy response in PTCH1-mutant basal cell carcinoma with squamous differentiation"],"prefix":"10.3389","volume":"17","author":[{"given":"Esranur","family":"Ayd\u0131n","sequence":"first","affiliation":[{"name":"Precision Oncology Center, Medicana Health Group","place":["Istanbul, 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