Age and sex: dual drivers remodeling the anti-tumor immune microenvironment and shaping personalized immuno-oncology

Abstract

Despite breakthrough advancements in cancer immunotherapy, significant inter-individual heterogeneity in clinical outcomes persists, bringing the regulatory roles of intrinsic host biological variables into sharp focus. Accumulating fundamental and clinical evidence indicates that age and sex play crucial roles in determining tumor susceptibility, disease progression, and the remodeling of the anti-tumor immune microenvironment. This review systematically delineates the profound impacts of the dual dimensions of age and sex on anti-tumor immune responses and immune evasion mechanisms. In the dimension of age, this article outlines the progressive functional decline of T/B lymphocytes and innate immune subsets driven by immunosenescence, and emphatically reveals how inflammaging and its associated senescence-associated secretory phenotype (SASP) orchestrate the formation of an immunosuppressive tumor microenvironment. In the dimension of sex, we deeply explore four core mechanisms comprising sex chromosome genomics (e.g., escape from X-chromosome inactivation and loss of Y chromosome), sex hormone networks, microenvironmental metabolic reprogramming, and the host gut microbiome, elucidating the molecular basis driving the disparities in innate and adaptive immunity between males and females. In summary, thoroughly deciphering the complex immune regulatory networks driven by age and sex not only helps elucidate the disparities in efficacy and toxicity observed in patients undergoing immune checkpoint inhibitors, but also provides crucial theoretical foundations and translational insights for the future development of “age-tailored” and “sex-specific” strategies in personalized immuno-oncology.