Characteristics and therapeutic resistance mechanisms of the prostate cancer immune microenvironment - Review

Sep 22, 2026

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The review examines how the immunosuppressive, “cold” tumor microenvironment of metastatic castration-resistant prostate cancer drives immunotherapy failure and therapeutic resistance. It positions the androgen receptor (AR) signaling pathway as the central regulator, describing effects on CD8+ T-cell cytotoxicity, expansion of immunosuppressive myeloid and regulatory T-cell compartments, and spatial heterogeneity of immune infiltration. It discusses biomarker-defined responsive subsets and emerging strategies, while emphasizing challenges in translating preclinical findings to human tumor ecology.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Introduction and research rationale

Epidemiology and current status of immunotherapy for prostate cancer

Clinical challenges of the immunologically ‘cold tumour’ phenotype

TYPE Review PUBLISHED 07 April 2026 DOI 10.3389/fphar.2026.1769271 OPEN ACCESS EDITED BY Dawei Chen, University of Kiel, Germany REVIEWED BY Janny A Villa-Pulgarin, Cornell University, United States Peng Huang, Sichuan University, China *CORRESPONDENCE Xiaoshuang Tang, [tangxiaoshuang@sina.com](tangxiaoshuang@sina.com) RECEIVED 16 December 2025 REVISED 24 February 2026 ACCEPTED 16 March 2026 PUBLISHED 07 April 2026 CITATION Li J, Wang X and Tang X (2026) Characteristics and therapeutic resistance mechanisms of the prostate cancer immune microenvironment: a comprehensive analysis from bench to clinic. Front. Pharmacol. 17:1769271 . doi: 10.3389/fphar.2026.1769271 COPYRIGHT © 2026 Li, Wang and Tang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Characteristics and therapeutic resistance mechanisms of the prostate cancer immune microenvironment: a comprehensive analysis from bench to clinic Jun Li 1, Xiong Wang 2 and Xiaoshuang Tang 3* 1Ankang Central Hospital, Ankang, Shaanxi, China, 2The Ankang Hospital for Maternity and Child Health, Ankang, Shaanxi, China, 3Department of Urology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China The immunosuppressive, ‘cold’ tumor microenvironment (TME) of metastatic castration-resistant prostate cancer (mCRPC) is a primary cause of immunotherapy failure. This review delineates the androgen receptor (AR) signalling pathway as the central orchestrator of therapeutic resistance. AR activation directly suppresses CD8+ T-cell cytotoxicity, expands immunosuppressive myeloid and regulatory T-cell compartments, and drives spatial heterogeneity in immune infiltration. We highlight that responsive patient subsets can be identified by specific biomarkers—such as biallelic CDK12 inactivation or DNA damage repair deficiencies—which guide the use of immune checkpoint or PARP inhibitors. Emerging agents, including mutationspecific AR degraders and bispecific T-cell engagers, show potential toreprogramme the TME. However, clinical translation remains challenging, limited by discrepancies between preclinical models and human tumour ecology, coupled with dynamic evolution under therapeutic pressure. Overcoming resistance will require an integrated strategy combining highresolution spatial multi-omics, advanced disease models, and biomarkerdriven trials focused on rational combinations that co-target the AR pathway. Prioritizing this mechanistic approach is therefore critical to advance precision therapy for prostate cancer. KEYWORDS androgen receptor, cold tumor, immune microenvironment, immunotherapy, prostate cancer, therapeutic resistance 1 Introduction and research rationale 1.1 Epidemiology and current status of immunotherapy for prostate cancer The progression of advanced prostate cancer to metastatic castration-resistant prostate cancer (mCRPC)–a lethal stage characterized by profound therapeutic resistance–is heavily influenced by an immunosuppressive tumor microenvironment (TME) (Lin et al., 2023a) . Although immunotherapy has transformed oncology, its success in mCRPC remains limited, reflecting the tumor’s “cold” phenotype (Lin et al., 2023b) . Immune checkpoint Frontiers in Pharmacology 01 [frontiersin.org](frontiersin.org) inhibitors (ICIs) show modest (~4–10%) monotherapy response rates, constrained largely by androgen receptor (AR) signaling which suppresses CD8+ T-cell function and upregulates PD-L1 . Other modalities face similar TME-mediated barriers: therapeutic vaccines (e.g., sipuleucel-T)

FAQs

How does the AR signaling pathway contribute to therapeutic resistance in mCRPC?

The review describes AR activation as suppressing CD8+ T-cell cytotoxicity, expanding immunosuppressive myeloid and regulatory T-cell compartments, and promoting spatial heterogeneity in immune infiltration, collectively supporting resistance to immunotherapy.

What defines an immunologically ‘cold’ tumor microenvironment in prostate cancer?

A ‘cold tumour’ is characterized by sparse infiltration of cytotoxic T lymphocytes and dominance of immunosuppressive cellular and molecular networks, enabling immune escape and limiting immune-mediated tumor elimination.

What strategies does the review suggest to overcome resistance and reprogram the TME?

It highlights biomarker-driven stratification and rational combination approaches, including emerging AR-targeting agents and T-cell engaging modalities, and notes the need for integrated methods such as spatial multi-omics, advanced disease models, and biomarker-driven trials.

Sep 22, 2026

Upload by Sarah