Hereditary cancer syndromes as a model for precision oncology: the paradigms of HRD and MSI

Abstract

Hereditary cancer syndromes such as BRCA-associated and Lynch syndrome have provided a clinical framework for understanding the molecular underpinnings of homologous recombination deficiency (HRD) and microsatellite instability (MSI). These phenotypes have reshaped precision oncology by enabling biomarker-driven use of PARP inhibitors and immune checkpoint inhibitors (ICIs). This review discusses the clinical relevance of HRD and MSI as therapeutic targets and predictive biomarkers across various tumor types, with an emphasis on approved agents and combination strategies. We detail the evolving landscape of resistance to PARP inhibitors and ICIs, and the emergence of novel targets within the DNA damage response (DDR) pathway, including ATR, WEE1, and DNA-PK. Beyond classical checkpoint blockade, we explore the therapeutic potential of next-generation immunosuppressive targets, LAG-3, TIGIT, TIM-3, and VISTA, as well as STING pathway activation as a means to convert immunologically “cold” tumors into responsive phenotypes. Finally, we review emerging biomarkers beyond MSI-H, such as POLE, TMB, and MBD4, that may broaden the scope of immunotherapy responsiveness. The study of hereditary cancer syndromes has provided a roadmap for molecularly targeted therapies and biomarker development. Integrating germline testing, somatic profiling, and functional assays will be essential to overcome resistance and implement more effective, personalized treatment strategies for patients.