Sexual Dimorphism in Cancer Immunotherapy Outcomes

Cancer immunotherapy has transformed the management of various malignancies, yet emerging evidence reveals that male and female patients frequently exhibit divergent responses. Biological sex modulates innate and adaptive immunity through genetic, hormonal and epigenetic mechanisms, affecting immune cell composition, cytokine production and antigen presentation. Tumour antigenicity and mutational burden often differ between men and women, influencing susceptibility to immune checkpoint blockade. Furthermore, sex-specific variations in the tumour microenvironment, including differential immune cell infiltration and metabolic profiling, contribute to distinct patterns of treatment efficacy and adverse events. Recognition of these differences underscores the need for sex-stratified clinical trials and personalised therapeutic strategies that account for hormonal status, genetic background and immune landscape to optimise outcomes across sexes.

Research from Nature Portfolio

Recent studies have employed large-scale molecular profiling to dissect sex-associated differences in immunotherapy responsiveness. One analysis of checkpoint inhibitor recipients revealed inconsistent conclusions from pooled clinical trials, prompting a deep dive into patient omics data. This work identified divergent immune-related gene expression and checkpoint molecule patterns across multiple cancer types, emphasising that sex biases in immune signatures may underlie variable treatment success. In a complementary investigation, researchers explored how MHC-based immune selection shapes tumour evolution in relation to sex and age. They demonstrated that younger and female individuals accumulate a higher proportion of poorly presented driver mutations, suggesting that neoantigen availability and selection pressure differ by sex. Together, these insights highlight that sex-specific molecular and immunological factors are critical determinants of immunotherapy outcome.

Sexual Dimorphism in Cancer Immunotherapy Outcomes publication trend

The graph below shows the total number of articles in sexual dimorphism in cancer immunotherapy outcomes across all publications each year (not limited to Nature Index journals).

Technical terms

Sexual dimorphism: Biological differences between males and females that influence physiology, immune function and disease outcomes.

Immune checkpoint inhibitor: A therapeutic antibody that blocks regulatory pathways in T cells to enhance antitumour immunity.

Tumour microenvironment: The local cellular and molecular milieu surrounding a tumour, including immune cells, stroma and signalling molecules.

Tumour mutational burden: The total number of somatic mutations per coding area of a tumour genome, used as a biomarker of neoantigen load.

Cytokine: A signalling protein secreted by immune cells that mediates inflammation, cell growth and immune modulation.

References

1. Sex-related differences in serum biomarker levels predict the activity and efficacy of immune checkpoint inhibitors in advanced melanoma and non-small cell lung cancer patients. Journal of Translational Medicine (2024).
2. Sex Differences in Cancer Immunotherapy Efficacy, Biomarkers, and Therapeutic Strategy. Molecules (2019).
3. Sex-associated molecular differences for cancer immunotherapy. Nature Communications (2020).
4. Strength of immune selection in tumors varies with sex and age. Nature Communications (2020).
5. Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials. Journal of Clinical Medicine (2018).