Pan-cancer analyses reveal that increased Hedgehog activity correlates with tumor immunosuppression and resistance to immune checkpoint inhibitors.

BACKGROUND Immune checkpoint inhibitors (ICIs) have shown numerous clinical benefits in multiple cancer types, but good predictive biomarkers are severely lacking. Although increasing evidence has linked Hedgehog (Hh) signaling pathway with tumor development, a systematic investigation for its potential as a biomarker remains elusive. METHODS We collected and analyzed the transcriptional data and clinical outcomes of diverse cancers from the Cancer Genome Atlas and four published ICI datasets. Hh activity was estimated by conducting a single-sample gene-set enrichment analysis (ssGSEA) for the Hh-related genes and calculating the ssGSEA score in each tumor sample. RESULTS Our findings suggest that tumors with high Hh activity displayed multiple immunosuppressive characteristics, including lack of anti-tumor response pathways, downregulation of immune effectors, enrichment of immunosuppressive cells and chemokines, and activation of immunosuppressive signaling. Notably, patients in the non-response group had enriched Hh activity and showed worse overall survival (OS; pooled HR = 1.50, 95% CI = 1.02-2.21, p = 0.039). In the subgroup of high programmed cell death ligand 1 (PD-L1) expression, patients who harbored high Hh activity displayed a dramatically lower response rate to ICIs and a strikingly worse OS (pooled HR = 2.89, 95% CI = 1.53-5.49, p < 0.001). CONCLUSION Increased Hh activity correlates with tumor immunosuppression across diverse cancers. Hh activity is not only a predictive biomarker for resistance to ICIs but can also better predict clinical outcomes in combination with PD-L1 expression.