A comprehensive review of sex differences in the clinical outcomes to immunotherapy on solid tumors

Immunotherapy has led to a paradigm shift in the treatment of various tumors. However, the results obtained sometimes show heterogeneous and inconsistent responses despite the presence of biomarkers such as PD-L1. Recent studies suggest that the efficacy of immunotherapy may vary based on sex, although the findings remain controversial. The aim of this comprehensive review is to evaluate the available evidence and the biological mechanisms that could explain these differences. Some recent meta-analyses have suggested a greater overall survival benefit for males. Theoretical models, supported by in vivo studies in different animal species, are currently focused on the implications of the tumor microenvironment, hormonal factors in the antitumor activity of the immune system and their correlation with the patient's sex. Other chromosomal sex-specific alterations could be influenced by epigenetic changes affecting genetic material. Prospective studies are needed to further investigate the uncertain relationship between sex and immunotherapy in humans.