Sexual Dimorphism in Immunity and Metabolism: Unraveling the Impact on Response to Cancer Immunotherapy

A recent observational study by Jin et al., found male sex and pretreatment weight loss to be associated with worse progression free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibition (ICI) [1]. Although sexual dimorphism in immunity is well established, recent studies have begun to elucidate the mechanisms by which sex-specific immunity contributes to diseases such as cancer, and autoimmunity [2-5]. Similarly, the complex interplay between gonadal hormones, sex-based gene expression, and metabolism, particularly immunometabolism and the subsequent ability to mount effective antitumor immunity is a burgeoning field of investigation [6,7]. Cancer cachexia, a multifactorial syndrome characterized by severe weight loss, muscle wasting, and systemic inflammation, further complicates the metabolic landscape of NSCLC, influencing treatment response and outcomes. Unlike obesity-associated cancers such as breast and colorectal cancer, where increased body mass index (BMI) is linked to higher cancer risk, NSCLC does not display this association [8]. Considering this distinction, we seek to frame the clinical findings of Jin et al., in NSCLC in the context of tripartite interactions between inflammation, metabolism, and the efficacy antitumor immunity potentiated by ICI.