How Age and Sex Reshape Your Immune System's Ability to Fight Cancer

Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed oncology — yet patient responses remain highly variable and poorly predicted by tumor mutational burden alone. This comprehensive review argues that two fundamental biological variables — age and biological sex — are underappreciated master regulators of anti-tumor immunity and immunotherapy efficacy.

On the aging dimension, the review details how immunosenescence progressively degrades every arm of the immune system. Dendritic cells lose antigen-uptake and T-cell priming capacity. Natural killer cells downregulate cytotoxicity receptors (NKp30, NKp46, NKp44) and reduce IFN-γ secretion. Macrophages polarize toward pro-tumorigenic phenotypes, secreting SASP factors like IL-10, CCL2, and CXCL13. T cells undergo thymic involution, TCR repertoire contraction, and emergence of CD28-negative exhausted subsets resistant to ICI reinvigoration. Critically, the review distinguishes senescent T cells (irreversible, ICI-refractory) from exhausted T cells (epigenetically distinct, ICI-responsive) — a clinically vital distinction that is often overlooked. B cells also decline, with impaired AID expression disrupting antibody affinity maturation.

Complicating matters further, aging co-occurs with inflammaging — a systemic, chronic, low-grade sterile inflammation. SASP-driven cytokines from senescent immune and stromal cells recruit MDSCs and Tregs, constructing a deeply immunosuppressive TME. This dual process of immune degeneration and immune overactivation creates a self-reinforcing cycle that accelerates tumor immune evasion in elderly patients.

On the sex dimension, the review explores four core mechanistic layers. First, sex chromosome genomics: females benefit from broader immune gene expression due to escape from X-chromosome inactivation, while males experience age-related loss of Y chromosome (LOY) in immune cells, impairing tumor surveillance. Second, sex hormone networks: estrogens generally enhance adaptive immunity and IFN responses, while androgens suppress immune activation — partly explaining why females mount stronger ICI responses but also suffer more immune-related adverse events. Third, metabolic reprogramming: sex-based differences in lipid metabolism, glucose utilization, and mitochondrial function within the TME alter immune cell fitness and tumor-promoting microenvironments differently in males versus females. Fourth, the gut microbiome: sex-differentiated microbial composition modulates systemic immune tone and ICI responsiveness, emerging as a tractable therapeutic target.

The clinical implications are substantial. Sex and age together explain a meaningful portion of the heterogeneity in ICI efficacy and toxicity. The review advocates for age-stratified and sex-stratified clinical trial designs, biomarker development, and ultimately personalized immuno-oncology protocols. Limitations include the review's scope being confined to adult aging, excluding pediatric and young adult oncology, and reliance on murine model data for some mechanistic claims.