Lineage plasticity-driven immunometabolic state transitions in advanced prostate cancer: biomarkers and therapeutic stratification.

Authors

Haowen Wu, Wei Zhang, Xin Yan, Kai Ma, Manuel Colucci, Qiang Dong, Pan Song

Published in

Seminars in immunopathology. Volume 48. Issue 1. Oct 20, 2026. Epub Oct 20, 2026.

Abstract

Advanced prostate cancer is commonly described as immunologically cold, yet that label obscures a disease continually remodelled by treatment. Androgen-receptor (AR) pathway inhibition, chemotherapy, DNA-damage-directed therapy and radioligand treatment select resistant clones while altering lineage identity, metabolic dependence, antigen presentation and metastatic niches. AR-high, AR-low, double-negative, amphicrine and treatment-emergent neuroendocrine phenotypes are therefore better viewed as evolving immunometabolic states than as fixed histologies. Here, we develop a lineage-metabolism-immunity framework that integrates metastatic biopsies, longitudinal sampling, single-cell and spatial analyses, functional imaging and mechanistic prostate cancer models. Lineage determines which metabolic programmes remain available; tumour, stromal and immune cells then compete for nutrients and exchange metabolites that shape antigen presentation, myeloid suppression and lymphocyte function. We focus on glucose and lactate, lipids, amino acids, hypoxia-adenosine signalling and epigenetically active metabolites, while separating patient evidence from causal prostate cancer models and pan-cancer inference. The framework reframes three clinical tasks: identifying the state driving progression, recognising transitions under therapy and selecting combinations that relieve the dominant immune bottleneck without disabling effector cells. Translation will require longitudinal, lesion-aware measurements that connect lineage markers to functional evidence of metabolic dependence and immune context. The goal is not a universal metabolic target, but a tractable intervention matched to the tumour state, metastatic site and therapeutic window.

PMID:
42902014
Bibliographic data and abstract were imported from PubMed on 21 Oct 2026.

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