Castration-resistant prostate cancer as an adaptive tumor ecosystem: coupling tumor evolution with microenvironmental reprogramming.

Abstract

Castration-resistant prostate cancer (CRPC) represents a lethal stage of prostate cancer that emerges following sustained androgen deprivation therapy (ADT) and remains a major clinical challenge in the era of androgen receptor (AR)-targeted therapies. Although AR reactivation and lineage plasticity are recognized as central mechanisms of resistance, these tumor-intrinsic processes alone cannot fully explain the profound heterogeneity and therapeutic failure observed during CRPC evolution. Here, integrating recent advances in single-cell and spatial profiling, we propose a unified framework in which CRPC is viewed as an adaptive tumor ecosystem shaped by evolutionary selection, cellular plasticity, and microenvironmental co-evolution under therapeutic pressure. ADT not only selects pre-existing resistant populations but also induces cellular reprogramming, expanding tumor state diversity and adaptive capacity. Concurrently, the tumor microenvironment is extensively remodeled to support and stabilize therapy-adapted states. Immune compartments evolve toward myeloid-dominant immunosuppressive configurations characterized by T cell dysfunction and exclusion, whereas cancer-associated fibroblasts (CAFs) promote tumor persistence through stromal remodeling, metabolic coupling, and alternative steroidogenic pathways. Neural remodeling represents an additional regulatory layer that enhances cellular plasticity, stress adaptation, and neuroendocrine differentiation. Together, these alterations establish a multicompartmental and self-reinforcing tumor-microenvironment network that sustains adaptation during AR suppression. This ecosystem framework further extends beyond the primary tumor to distal niches, including bone metastases and the gut microbiome, where tumor-osteoblast-osteoclast interactions and microbial regulation of androgen metabolism and immunity contribute to therapeutic adaptation. By integrating tumor evolution with immune, stromal, neural, and distal ecosystem remodeling, this perspective provides a system-level framework for understanding CRPC progression and highlights therapeutic strategies aimed at reprogramming or destabilizing adaptive tumor ecosystems rather than targeting individual resistance pathways alone.