Sex Matters: Hormonal and Chromosomal Determinants of Autoimmunity and Anti-Cancer Immunity Across the Lifespan.

Biological sex plays a key role in shaping both anti-cancer immunity and autoimmunity through multiple distinct mechanisms.

• Identified biological factors underlying sexual dimorphism include sex differences in hormone levels, chromosome complement, and expression of the long non-coding RNA XIST.
• These factors alter immune responses against cancer as well as autoimmune responses against healthy tissues.
• The review identifies these factors as operating across multiple aspects of both anti-cancer immunity and autoimmunity.

Hormone levels undergo significant changes across the lifespan that affect immune function.

• Key hormonal transitions identified include mini-puberty, menopause, and andropause.
• These hormonal changes are discussed in the context of how they affect both anti-cancer immunity and autoimmunity.
• The review frames these changes as dynamic rather than static contributors to immune sexual dimorphism.

Somatic alterations in chromosomal complement, specifically loss of Y (LOY) chromosome, accumulate across the lifespan and affect immunity.

• Loss of Y (LOY) chromosome is identified as a somatic chromosomal alteration that accumulates over time.
• LOY is discussed in the context of its effects on anti-cancer immunity and autoimmunity.
• Chromosomal complement changes are presented alongside hormonal changes as lifespan-dependent modulators of immune responses.

Expression of the long non-coding RNA XIST is identified as a chromosomal determinant of immune sexual dimorphism.

• XIST is specifically named as a factor contributing to sex differences in immune responses.
• XIST is categorized alongside hormone levels and chromosome complement as a biological factor underlying sexual dimorphism.
• Recent advances in understanding XIST's role are described as part of newly identified mechanisms of sex-based immune differences.

Understanding sex-based immune differences is expected to inform immunotherapeutic approaches that optimize anti-cancer immunity while controlling autoimmune responses.

• The authors state these recent advances 'will set the stage for identifying immunotherapeutic approaches that optimize anti-cancer immunity while controlling the autoimmune responses.'
• The dual goals of maximizing anti-tumor immunity and minimizing autoimmunity are framed as potentially addressable through sex-informed strategies.
• The review positions lifespan changes in sex-related biological factors as clinically relevant to immunotherapy development.