Biological sex-dependent hormonal signaling and metabolomic profiles in obesity alter tumor microenvironment and immunotherapy outcomes
Commonly viewed as a negative prognostic factor in cancer, obesity is associated with improved responses to cancer immunotherapy using immune checkpoint inhibitors (ICIs). Although data suggest a sexual dimorphism influencing the effects of obesity on immunotherapy responses, to our knowledge, the intersection of sex and obesity on immunotherapy requires further exploration. We demonstrate, in a pan-cancer analysis stratified by sex and BMI, that obesity (BMI ≥ 30) is associated with improved survival after ICI only in male patients. In preclinical models of diet-induced obesity (DIO), we observed that only DIO male tumor-bearing mice responded better to ICI. The differential effect of sex on outcomes was associated with alterations in the tumor microenvironment where DIO female mice demonstrated increased tumor-associated macrophages skewed toward a M2 phenotype. Ovariectomy of DIO female mice reduced M2 polarization and increased anti-tumor immune responses including increases in tumor-infiltrating T cells following ICI. Metabolomic analysis of DIO mice demonstrated distinct profiles base on sex. Re-stratification of female cancer patients revealed that obesity was associated with improved outcome, but only in post-menopausal (age ≥ 55) patients. We identify that the immunotherapy “obesity paradox” is sex-dependent and that hormonal and metabolomic status modulates the influence of obesity on ICIs.
Authors
- Spencer R. Rosario (ORCID: https://orcid.org/0000-0002-2626-9257)
- Ryan N. Nielsen
- Hossein Borghaei (ORCID: https://orcid.org/0000-0002-2577-4454)
- Emmanuel S. Antonarakis (ORCID: https://orcid.org/0000-0003-0031-9655)
- Lam T. Khuat (ORCID: https://orcid.org/0000-0002-4223-8805)
- Sami Ibrahimi (ORCID: https://orcid.org/0000-0002-7538-346X)
- Logan Vahid Vick (ORCID: https://orcid.org/0009-0006-9778-0120)
- William J. Murphy (ORCID: https://orcid.org/0000-0002-2793-401X)
- Sara K. Vesely (ORCID: https://orcid.org/0000-0003-3448-0156)
- Shuchi Gulati (ORCID: https://orcid.org/0000-0001-6793-9694)
- Michael G Machiorlatti (ORCID: https://orcid.org/0000-0002-9180-3647)
- Aryana M. Razmara (ORCID: https://orcid.org/0000-0002-3834-3442)
- Nishant S. Gandhi (ORCID: https://orcid.org/0009-0003-0560-5543)
- Arta Monir Monjazeb (ORCID: https://orcid.org/0000-0001-5175-8004)
- Sean James Judge (ORCID: https://orcid.org/0000-0002-1842-9468)
- Sarbajit Mukherjee (ORCID: https://orcid.org/0000-0003-2153-3896)
- Wahed A. Firoz (ORCID: https://orcid.org/0009-0005-3798-3818)
- Michael K. Sheng
- Raid M. Aljumaily
- Craig P. Collins
- Yao-Hui Sun (ORCID: https://orcid.org/0000-0002-3716-6659)
- Yatian Yang
- Andrew Elliott (ORCID: https://orcid.org/0000-0001-8494-8031)
- Robert J. Canter
- Ziming Wang
Institutions
- Fox Chase Cancer Center (US)
- Baptist Hospital of Miami (US)
- Roswell Park Comprehensive Cancer Center (US)
- University of Minnesota (US)
- Caris Life Sciences (United States) (US)
- University of California Davis Medical Center (US)
- Masonic Cancer Center (US)
- University of Oklahoma Health Sciences Center (US)
- University of California, Davis (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-11-03
- DOI
- https://doi.org/10.1172/jci203453
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00