Work

Clinically oriented immune heterogeneity in prostate cancer: emerging targets and strategies

Year: 2026

Type: article

Abstract: Prostate cancer (PCa) has long been viewed as an immunologically "cold" malignancy because immune checkpoint inhibitors (ICIs) show limited benefit in unselected patients, particularly after progression to metastatic castration-resistant PCa (mCRPC) or treatment-related neuroendocrine PCa (NEPC). Single-cell and spatial profiling now reveal immune heterogeneity across patients, between lesions, and along the path from localized disease to metastasis. Primary tumors form mosaics of immune-excluded glands, myeloid-suppressed stromal borders, and focal lymphocyte-rich niches with B-cell aggregates and tertiary lymphoid structures (TLS). TLS-high regions represent an actionable "hot minority" resembling inflamed, ICI-responsive cancers, supporting biomarker-guided neoadjuvant or focal immunotherapy. With dissemination, heterogeneity expands across sites; bone metastases become marrow immune organs dominated by suppressive macrophage/monocyte programs and dysfunctional T cells, often driven by the CCL2-CCR6 axis. Standard therapies remodel these ecosystems, creating inflammatory windows yet fostering adaptive resistance. Mechanistically, myeloid-driven, inflammation-coupled rewiring is central to escape: IL-8/CXCR2 signaling and therapy-induced senescence/SASP recruit and polarize suppressive myeloid cells, reinforcing T-cell exclusion and exhaustion. Variable HLA class I loss and hypoxic or metabolic "functional cold zones" add lesion-specific immune invisibility. Clinically, these insights motivate a heterogeneity-aware framework integrating genomic responder subsets with microenvironmental stratification. Barrier-matched strategies include T-cell redirection (PSMA/STEAP1 engagers, bispecifics, CAR-T) and combinations that heat or modulate myeloid cells. Treating immune heterogeneity as a clinical variable enables durable immunotherapy in PCa.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1753718