The CTSZ-TRA2A-IL32 axis defines a targetable macrophage-dependent pathway in metastatic prostate cancer.

BACKGROUND: Emerging evidence underscores the pivotal role of M2-polarized tumor-associated macrophages (M2-TAMs) in orchestrating immunosuppressive tumor microenvironments that fuel metastatic dissemination in prostate cancer (PCa), yet the fundamental mechanisms governing M2-TAM trafficking in lethal PCa progression remain poorly understood. METHODS: Multi-cohort transcriptomic analyses were performed to identify metastasis-associated genes, with CTSZ prioritized as a key cathepsin linked to prostate cancer progression. Circulating tumor and bone metastatic mouse models were employed to investigate CTSZ-driven M2-TAM infiltration and metastatic behavior. Mechanistic studies included proteasomal degradation assays, IL32 pre-mRNA splicing analysis, and IL-32 binding experiments using RGD motif-dependent interactions. Therapeutic efficacy was tested with the ITGA5 inhibitor GLPG0187 in preclinical models. RESULTS: Elevated CTSZ expression shows strong clinical association with advanced pathological progression. CTSZ overexpression in PCa cells drives lung metastasis dissemination and bone metastatic in vivo model but fails to enhance cell-intrinsic oncogenic behaviors in vitro systems. Overexpression of CTSZ promotes M2-TAM infiltration and metastasis by inducing TRA2A degradation via the proteasome pathway, which alleviates TRA2A-mediated suppression of IL32 alternative splicing. Enhanced IL-32 secretion facilitates M2-TAM recruitment through binding to macrophage integrin ITGA5. Pharmacological inhibition of ITGA5 with GLPG0187 significantly reduced metastatic burden and M2-TAM infiltration in vivo. CONCLUSIONS: The CTSZ/TRA2A/IL-32/ITGA5 axis orchestrates protumoral immunity in PCa metastasis by driving M2-TAM recruitment. Targeting this pathway, particularly through ITGA5 blockade, represents a promising therapeutic strategy to inhibit metastatic progression and remodel the immunosuppressive tumor microenvironment.