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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI203453

Biological sex-dependent hormonal signaling and metabolomic profiles in obesity alter tumor microenvironment and immunotherapy outcomes

Logan V. Vick,1 Spencer R. Rosario,2 Ziming Wang,1 Craig Collins,1 Lam T. Khuat,1 Yatian Yang,3 Michael K. Sheng,1 Wahed A. Firoz,1 Ryan N. Nielsen,1 Yao-Hui Sun,4 Aryana M. Razmara,5 Hossein Borghaei,6 Emmanuel S. Antonarakis,7 Andrew Elliott,3 Nishant Gandhi,3 Raid Aljumaily,8 Sami Ibrahimi,8 Michael Machiorlatti,9 Sara K. Vesely,9 Shuchi Gulati,10 Sarbajit Mukherjee,11 Robert J. Canter,5 Sean J. Judge,5 Arta M. Monjazeb,4 and William J. Murphy1

1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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1Department of Dermatology, UC Davis School of Medicine, Sacramento, United States of America

2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Radiation Oncology, University of California Davis Comprehens, UC Davis School of Medicine, Sacramento, United States of America

5Department of Surgery, Division of Surgical Oncology, University of Califor, UC Davis School of Medicine, Sacramento, United States of America

6Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, United States of America

7Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America

8Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

9Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

10Department of Internal Medicine, Division of Hematology/Oncology, UC Davis School of Medicine, Sacramento, United States of America

11Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, United States of America

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Published November 3, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI203453.
Copyright © 2026, Vick et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 3, 2026 - Version history
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Abstract

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.

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