The Impact of the Tumor Microenvironment on Immune Checkpoint Inhibitor Resistance in Prostate Cancer: Mechanistic Insights and Therapeutic Strategies.

Abstract

While immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for melanoma and lung cancer, their efficacy in prostate cancer (PCa) remains limited. This therapeutic resistance is linked in part to the "cold" immunophenotype of PCa, which is orchestrated by a highly immunosuppressive tumor microenvironment (TME). Current evidence suggests that distinct spatial barriers and metabolic dysregulation within the TME actively exclude effector lymphocytes and induce exhaustion. Here, we dissect these multidimensional resistance mechanisms, ranging from myeloid cell plasticity to stromal stiffening. We further evaluate how clinical paradigms are shifting from monotherapy to rational combinations, such as those involving poly(ADP-ribose) polymerase (PARP) inhibitors or anti-angiogenic agents, designed to reprogram the TME. Finally, by exploring emerging frontiers including neuroendocrine transdifferentiation, nanobiotechnology, and liquid biopsy, we propose a roadmap for next-generation therapies aimed at sensitizing PCa to immune recognition.