Tumor-associated macrophages and lineage plasticity in prostate cancer: from established myeloid programs to emerging spatial hypotheses

Abstract

Androgen receptor signaling inhibitors (ARSIs) have transformed the treatment of advanced prostate cancer, yet durable responses are limited by the emergence of therapy-resistant disease states, including neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC). Lineage plasticity has traditionally been studied from a tumor-cell-intrinsic perspective, but single-cell and spatial studies increasingly indicate that the tumor microenvironment, particularly tumor-associated macrophages (TAMs), may influence tumor-cell state transitions, immune exclusion, and therapeutic resistance. In this review, we synthesize established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity. We first summarize independently supported myeloid programs, including SPP1+/TREM2+ macrophage states and TAM-derived pathways such as IL-6/STAT3, TGF-beta, NF-kappaB, CXCL12/CXCR4, and adenosine signaling. We then discuss PLAC8+ TAMs, TNFAIP8L2, and PLAC8+ TAM/CXCL12+ iCAF/CD8+ TRM spatial aggregates as an emerging, hypothesis-generating framework that may be associated with ARSI-induced DNPC-like remodeling. Importantly, we explicitly distinguish spatial and transcriptomic associations from experimentally proven causal mechanisms. The proposed TNFAIP8L2-integrin/PI3K-Akt/beta-catenin/FOSL1-HMGA1 cascade is therefore presented as a working model that requires direct biochemical, genetic, and in vivo validation. Finally, we outline an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.