The dual immune landscape of homologous recombination-deficient tumors: mechanisms and therapeutic implications.

Abstract

Homologous recombination deficiency (HRD) is a major genomic feature of several malignancies and provides a therapeutic rationale for DNA-damaging agents and PARP inhibitors. Beyond its role in genome instability, accumulating evidence suggests that HRD also reshapes the tumor microenvironment (TME). However, the immune consequences of HRD are not uniformly stimulatory. HRD-associated tumors may exhibit DNA damage-driven innate immune activation, increased interferon signaling, and enhanced antigen presentation, while simultaneously developing adaptive immune-evasive programs, including T-cell dysfunction, myeloid and regulatory T-cell recruitment, stromal remodeling, and vascular barriers to immune infiltration. In this review, we summarize current evidence linking HRD to immune activation and immune suppression across tumor types and propose a dual immune framework for understanding HRD-associated TME remodeling. We further discuss why HRD alone is insufficient to predict responses to immune checkpoint blockade and highlight emerging therapeutic strategies that integrate DNA damage response targeting with immune and stromal modulation.