Sex-specific and Sex Hormonal-Related Differences in Melanoma Microenvironment

Growing interest has emerged in the role of sex, as a biological variable that influence the immunopathogenesis of melanoma. Female patients exhibit significantly better disease outcomes compared to males, and antitumor immune responses and benefits of immunotherapy also differ between males and females. Preclinical and clinical studies suggest an association with a more immunogenic tumor microenvironment in women. However, the extent of sex- related differences in immune responses in melanoma remains unclear, highlighting the need for further research. Sex hormones play a role in determining the nature of melanoma tumor microenvironment, as estrogens and androgens have been shown to modulate immune responses, contributing to the differences observed between males and females. The generally more reactive and efficient female immune system may contribute to better antitumor responses. Conversely, males tend to have higher cancer incidence, potentially due to inherent immune-cellular and molecular variations. This review summarizes key findings on the influence of sex on melanoma in general, and more specifically on the melanoma tumor microenvironment and antitumor immune responses, to provide a comprehensive understanding of how sex influence melanoma progression and patients outcomes. Understanding these differences is crucial for developing more effective, personalized treatment strategies for melanoma patients.