Integrating homologous recombination deficiency and replication stress: converging strategies unlocking new frontiers in precision oncology

Homologous recombination (HR) deficiency (HRD) and replication stress (RS) are increasingly recognized as interconnected hallmarks of genomic instability in cancer, offering promising avenues for therapeutic targeting. As novel combination therapies targeting these hallmarks continue to emerge, understanding how these processes interact in therapeutic contexts and comparing the relative efficacy and toxicity of combination therapy is critical in advancing precision oncology. We investigate current and emerging assays that assess HRD and RS in cancer treatment and provide an exploration of related pathways. We also provide a high-level comparative pan-cancer analysis from results available on clinicaltrials.gov for common mono poly(ADP-ribose) polymerase inhibitor (PARPi), RS, and immune checkpoint blockade (ICB) therapies as well as their pairwise combinations, demonstrating efficacy and toxicity of current combination therapies. Integrating functional assessment of HRD and RS with immune contexture and considering these processes as outputs of their interconnected pathways in response to targeted agents could establish a unified therapeutic axis. Targeting this collective axis comprehensively may provide a promising foundation for next-generation, functionally guided treatment strategies capable of achieving durable responses with acceptable toxicity across diverse cancer types.