Molecular stratification of prostate cancer through sensory perception-related multi-omics analysis reveals chemoresistant mechanisms.

Background: Advanced prostate cancer (PCa) displays significant genetic heterogeneity and therapy resistance, yet the role of sensory perception pathways in its progression remains unclear.

Methods: We performed an integrative multi-omics analysis of sensory perception-linked mRNAs and lncRNAs from TCGA and scRNA-seq data. Unsupervised consensus clustering defined three molecular subtypes (CS1-CS3). Key biomarkers were validated in patient tissues and serum. Immune and stromal infiltration were quantified using TIDE and ESTIMATE. Single-cell trajectories characterized TSC22D3-positive T cells, and NicheNet mapped ligand-receptor interactions.

Results: Three subtypes emerged, with CS1 showing the poorest prognosis, marked chemotherapy resistance, and pronounced stromal-immune crosstalk. CS1 tumors exhibited elevated B- and T-cell infiltration and increased oxidative phosphorylation in TSC22D3-positive T cells. NicheNet analysis identified the TNF-CCL20 axis as a central mediator of immunosuppressive signaling and chemoresistance in CS1.

Conclusions: This study establishes sensory perception-associated molecular subtypes in PCa and links CS1 chemoresistance to immune microenvironment reprogramming via TNF-CCL20 signaling. These findings offer mechanistic insights into PCa progression and suggest actionable targets to overcome therapeutic resistance.