From cold to hot: A 'Prime, Activate, Sustain' framework for precision remodeling of the tumor microenvironment in...

Metastatic castration-resistant prostate cancer (mCRPC) is characterized by an immunologically "cold" tumor microenvironment (TME), which constitutes the primary barrier to effective immunotherapy. This systematic review synthesizes current evidence to deconvolute the multi-layered immunosuppressive landscape of the prostate TME and evaluates the expanding therapeutic arsenal designed to remodel it. We critically appraise the limited success of immune checkpoint inhibitor (ICI) monotherapy and highlight the emerging promise of novel modalities, including bispecific T-cell engagers (TCEs) and radioligand therapy (RLT). Notably, we highlight that rational combination and sequential strategies are essential, as evidenced by pivotal trials like CONTACT-02, which validate that tyrosine kinase inhibitors (TKIs) can modulate the immunosuppressive TME to enhance the clinical efficacy of immune checkpoint inhibitors (ICIs). Building upon this, we propose a novel 'Prime, Activate, Sustain' (PAS) framework-a temporally-sequenced therapeutic paradigm. This model advocates for a structured approach: initially disrupting the immunosuppressive niche ("Prime") with targeted agents (e.g., TKIs, AR inhibitors), followed by robust immune engagement ("Activate") with immunotherapies (e.g., ICIs, TCEs), and finally maintaining durable responses through adaptive monitoring ("Sustain"). The future of overcoming immunotherapy resistance lies in precision immuno-oncology, which integrates deep molecular profiling, AI-driven insights, and dynamic biomarker monitoring (e.g., ctDNA) to guide these rationally sequenced, multi-modal regimens, particularly in earlier disease stages. The proposed "Prime, Activate, Sustain" framework and the therapeutic strategies to enable it are synthesized in the accompanying figures.