Variants in immune-related genes and their association with breast cancer risk and clinical behavior: an integrative review

Breast cancer exhibits substantial clinical and molecular heterogeneity, partly shaped by interactions between tumor biology and the host immune system. Germline variants in immune-related genes may influence inflammatory tone, immune regulation, and tumor-immune interactions. However, evidence linking inherited immune genetic variation to breast cancer risk and clinical behavior remains fragmented and heterogeneous across studies. We conducted a structured integrative review of 33 human genetic associations evaluating germline variants in immune-related genes and their associations with breast cancer risk, prognosis, and clinicopathological features. Data were synthesized using a comparative, pathway-oriented analytic framework. Variants in cytokine genes, particularly TGFB1, IL6, IL1B, and IL10, were the most frequently associated with susceptibility, although effect directions varied across populations and genetic models. In contrast, variants in chemokine pathways (CXCL12) and immune checkpoint regulator genes (B7-H4/VTCN1, PD-1/PDCD1) showed consistent associations with tumor progression, immune evasion, and subtype-specific clinical features, including human epidermal growth factor receptor 2 (HER2)-positive disease and metastatic presentation. Across studies, substantial heterogeneity was observed, driven by differences in ethnic composition, sample size, methodological design, and deviations from the Hardy-Weinberg equilibrium. The findings support a pathway-oriented interpretation in which germline immune variation differentially influences immune regulation and tumor progression rather than uniformly determining disease risk. While inflammatory and immunoregulatory pathways appear to shape basal immune tone, immune effector function is less consistently associated with germline variation. Further progress will require extensive, multiethnic studies integrating genetic, transcriptomic, and functional data to clarify how inherited immune variation contributes to breast cancer biology.