Integrative multi-omics reveals the POSTN+ CAF–APOE+ macrophage axis drives immunosuppression and progression in prostate cancer

Abstract

Background The progression of prostate cancer to lethal castration-resistant (CRPC) and metastatic (mCRPC) stages is driven by a profoundly remodeled tumor microenvironment (TME). However, the identity of key stromal cell populations, their developmental dynamics, and their precise crosstalk with immune cells remain incompletely understood, limiting our ability to target the TME therapeutically. Methods We integrated single-cell RNA sequencing (scRNA-seq) data from 222,529 cells across 10 studies, encompassing normal prostate, primary tumors, CRPC, and mCRPC. Fibroblast heterogeneity was resolved using unsupervised clustering, trajectory inference (Monocle2), and regulon analysis (pySCENIC). Intercellular communication was deciphered using CellChat. Spatial transcriptomic data were integrated via CellTrek and SpaGene for validation. Clinical associations were evaluated in multiple bulk transcriptomic cohorts (e.g., TCGA-PRAD, IMvigor210) and extended to a pan-cancer atlas of 11 tumor types. Results We identified a distinct POSTN+ CAF subset that was progressively enriched in advanced disease. Trajectory analysis positioned POSTN+ CAFs as a progenitor-like state potentially transitioning toward inflammatory or contractile subtypes, with STAT1-centered regulon activity associated with this process. POSTN+ CAFs created an extracellular matrix (ECM)-remodeled, immune-excluded niche, correlated with elevated T-cell exclusion scores. We further uncovered a predicted communication axis where POSTN+ CAFs are computationally inferred to interact with M2-like, immunoregulatory APOE+ macrophages via the MDK-NCL ligand-receptor pair. The co-occurrence of POSTN+ cancer-associated fibroblasts and APOE+ macrophages correlated with worse patient outcomes. In the IMvigor210 urothelial carcinoma cohort (as indirect cross-cancer evidence), high co-infiltration was associated with diminished anti-PD-L1 response, although this finding requires validation in prostate cancer-specific cohorts. Exploratory pan-cancer analysis suggested conserved enrichment and adverse prognostic impact of this stromal-immune axis across diverse tumor types, though tissue-specific context should be considered. Conclusions Our integrated single-cell atlas defines a critical POSTN+ CAF–APOE+ macrophage unit that is associated with a fibrotic and immunosuppressive TME in advanced prostate cancer. If functionally validated, targeting this stromal-immune crosstalk axis could represent a promising therapeutic strategy to remodel the TME and overcome treatment resistance, although this remains speculative at present.