Sex-specific differences in cancer immunotherapy: need for male and female tailored strategies
Sex differences in immunotherapy, a hidden challenge
Evidence is increasing that the immune system exhibits subtle yet important differences between men and women. These differences can influence cancer incidence, tumor microenvironment (TME) composition, and responses to immunotherapy. Notably, sex-related differences in therapeutic efficacy are evident in non‑small cell lung cancer (NSCLC) and melanoma.
Hormones, chromosomes, and mechanisms explored
The research team compared TME composition by sex in both human and animal models. Levels of testosterone and estrogen, as well as X‑ and Y‑chromosome‑linked genes, were found to regulate immune cell activity, and external factors such as smoking, diet, and UV exposure also acted synergistically. Integrating these multilayered factors, they constructed a mechanistic model.
Clinical outcomes: monotherapy benefits men, combination therapy benefits women
Some clinical trials showed that men derived a larger benefit from monotherapy immunotherapy compared with chemotherapy, whereas women obtained greater advantage from combination chemo‑immunotherapy. However, not all studies yielded consistent results, so interpretation remains cautious.
Future therapeutic strategies: sex‑tailored immunotherapy
Accurately delineating sex differences requires clinical trial designs that include large patient cohorts. Going forward, developing immunotherapy protocols optimized for each sex will enable all patients to receive maximal benefit.
Accumulating evidence suggests that the immune system shows subtle but relevant differences between men and women. These differences may have an impact on cancer development and TME composition as well as responses to and adverse events elicited by immunotherapies. Several, albeit not all, clinical trials indicate a greater benefit from mono-immunotherapies over chemotherapies for male patients than for female patients, especially in non-small cell lung cancer and melanoma. Vice versa, female patients might benefit more from chemo-immunotherapies. In human as well as animal models, sex differences in cancer microenvironment composition were described, with partially divergent results. Sex-specific factors such as the levels of hormones, in particular testosterone and estrogen, or X- or Y-chromosome associated genes are likely to drive the observed differences, but are often confounded by external influences such as smoking behavior, diet, or UV exposure. Therefore, large clinical and mechanistic knowledge gaps remain regarding the influence of sex on cancer immunotherapies and strategies to optimize response in either sex. More clinical as well as experimental research in this field is required to close these knowledge gaps, and clinical trials should include large enough groups of male and/or female patients to allow robust sex-specific analyses.
This research addresses the real issue that men and women require distinct immunotherapy strategies. Widespread adoption of personalized treatment is expected to increase therapeutic success rates and reduce adverse effects.