Sex hormones and immune response: new therapeutic perspectives against cancer

Immunotherapies, while revolutionizing the treatment of many solid tumors, are not equally effective in all patients. In particular, numerous studies highlight a differing therapeutic response between the sexes: a recent meta-analysis of immune checkpoint inhibitors revealed that survival benefits were greater in men than in women.

This phenomenon has also been confirmed by Humanitas researchers, who have been studying the different responses of men and women to cancer immunotherapies thanks to a project supported by the Humanitas Foundation for Research. The researchers also reported a significant underrepresentation of women in clinical trials on immune checkpoint inhibitors over the past ten years, a phenomenon that has led to our partial understanding of immune responses in females. It is now crucial to close this knowledge gap and find solutions to improve the effectiveness of immunotherapies in women as well.

Fabio Conforti, assistant professor at Humanitas University and a medical oncologist at Humanitas Gavazzeni, and Professor Alberto Mantovani, President of the Humanitas Foundation for Research and Emeritus Scientific Director at Humanitas Research Hospital, addressed the topic in a recent review published in Cancer Cell. The authors propose that, in addition to tumor factors, sex hormones—especially their impact on the tumor microenvironment—may influence the effectiveness of immunotherapies. This discovery could explain the difference in efficacy between the sexes and suggests that manipulating sex hormones could improve responses to immunotherapies, thus offering a more targeted and effective therapeutic strategy.

The gender gap in clinical research: the underrepresentation of women

Historically, women have been underrepresented in clinical research, especially in studies on immunotherapeutics. Concerns about the risk of immune-related adverse events, particularly in patients with autoimmune diseases, have contributed to their exclusion from trials, as women represent 80% of patients with these conditions.

As Fabio Conforti pointed out: “This lack of inclusion has hindered a proper understanding of immune responses in female patients, delaying the discovery of differences in response to immunotherapeutics. Moreover, even in studies where women are better represented, data are often not disaggregated, making it impossible to draw sex-specific conclusions.”

Hormones as determinants in the effectiveness of immunotherapy

One of the key aspects emerging from the literature analysis conducted by the Humanitas team is the role of sex hormones in modulating the immune response. “Hormones, particularly estrogen and androgens, strongly influence immune responses, promoting immune suppression mechanisms in the tumor microenvironment,” explains Alberto Mantovani. “This is why hormonal fluctuations, typical of the menstrual cycle and menopause in women, could interfere with the effectiveness of immunotherapies.”

Sex hormones may therefore be crucial in understanding the differences between the sexes in response to cancer treatments. At the same time, they could offer a new therapeutic strategy.

What to do now: manipulating sex hormones and immunotherapy

Manipulating sex hormones in combination with immunotherapy represents a promising new therapeutic frontier. The authors of the review suggest that “targeting sex hormones could be a promising strategy to enhance the effectiveness of immunotherapy, paving the way for personalized treatments that take into account sex-specific and hormonal factors.”

However, this approach presents several methodological challenges. The main difficulty lies in the complex interaction between sex, sex hormones, and immune response, which varies significantly between men and women and is still not well understood.

“Further research is needed to explore how genetics, physiology, diseases, and lifestyle interact with sex hormones, thus influencing the immune response to tumors. More inclusive clinical trials are also required, considering sex differences in response to immunotherapy,” conclude Fabio Conforti and Alberto Mantovani. “To promote equitable and effective therapeutic strategies for all patients, the support of regulatory agencies and close multidisciplinary collaboration between oncologists, immunologists, endocrinologists, and statisticians will be essential.”