Hallmarks of Sex Bias in Immuno-oncology: Mechanisms and Therapeutic Implications

Sex differences are present across multiple non-reproductive organ cancers, with male individuals generally experiencing higher incidence of cancer with poorer outcomes. Although some mechanisms underlying these differences are emerging, the immunological basis is not well understood. Observations from clinical trials also suggest a sex bias in conventional immunotherapies with male individuals experiencing a more favourable response and female individuals experiencing more severe adverse events to immune checkpoint blockade. In this Perspective article, we summarize the major biological hallmarks underlying sex bias in immuno-oncology. We focus on signalling from sex hormones and chromosome-encoded gene products, along with sex hormone-independent and chromosome-independent epigenetic mechanisms in tumour and immune cells such as myeloid cells and T cells. Finally, we highlight opportunities for future studies on sex differences that integrate sex hormones and chromosomes and other emerging cancer hallmarks such as ageing and the microbiome to provide a more comprehensive view of how sex differences underlie the response in cancer that can be leveraged for more effective immuno-oncology approaches.