{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T05:14:45Z","timestamp":1783401285920,"version":"3.54.6"},"reference-count":85,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Effective treatment of endometrial cancer (EC) is frequently challenged by therapeutic resistance, immunosuppressive tumor microenvironments (TME), and patient comorbidities such as hypertension, kidney dysfunction, and metabolic syndrome. While molecular targeted therapies and immunotherapies (e.g., PD-1 blockade) have emerged as transformative approaches, variable drug sensitivity\u2014often exacerbated by the systemic inflammatory and uremic burden of comorbidities\u2014remains a significant hurdle. Building on the integration of molecular oncology and clinical translation, this review examines physical activity not merely as a preventive measure, but as a systems-level molecular modulator capable of enhancing drug sensitivity and immunotherapy efficacy. We synthesize evidence distinguishing preclinical findings from clinical reality, demonstrating that exercise remodels the TME by repolarizing Tumor-Associated Macrophages (TAMs), reducing Myeloid-Derived Suppressor Cells (MDSCs), and enhancing cytotoxic T cell infiltration. Furthermore, we discuss how exercise-induced shear stress promotes eNOS phosphorylation to normalize tumor vasculature and improve renal perfusion, thereby enhancing drug delivery and mitigating nephrotoxicity. We propose an integrated \u201cEC-Comorbidity Continuum\u201d perspective where personalized exercise prescriptions\u2014distinguishing between acute perfusion benefits and chronic immune priming\u2014serve as a non-pharmacological adjuvant to optimize molecular responses and overcome multidrug resistance.<\/jats:p>","DOI":"10.3389\/fonc.2026.1791875","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:23:10Z","timestamp":1783398190000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Physical activity as a molecular modulator to enhance immunotherapy and drug sensitivity in the endometrial cancer\u2013comorbidity continuum"],"prefix":"10.3389","volume":"16","author":[{"given":"Jing","family":"Wang","sequence":"first","affiliation":[{"name":"School of Sports Science and Engineering, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Sports Science and Engineering, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Sports Science and Engineering, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghao","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Sports Science and Engineering, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Sports Science and Engineering, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyun","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Sports Science and Engineering, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinming","family":"Ye","sequence":"additional","affiliation":[{"name":"School of Sports Science and Engineering, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Du","sequence":"additional","affiliation":[{"name":"School of Sports Science and Engineering, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00323-3","article-title":"Endometrial cancer","volume":"399","author":"Crosbie","year":"2022","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.29054\/apmc\/2024.1551","article-title":"Silent threats unveiled: Navigating the landscape endometrial cancer in women over 50 - a comprehensive analysis of post-menopausal bleeding as a crucial diagnostic indicator","volume":"18","author":"Sharif","year":"2024","journal-title":"Apmc"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071766","article-title":"Endocrine risk factors of endometrial cancer: Polycystic ovary syndrome, oral contraceptives, infertility, tamoxifen","volume":"12","author":"Ignatov","year":"2020","journal-title":"Cancers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.12775\/JEHS.2024.76.56569","article-title":"An overview of endometrial cancer risk factors","volume":"76","author":"\u017bycho\u0144","year":"2024","journal-title":"J Educ Health Sport"},{"key":"B5","doi-asserted-by":"publisher","first-page":"0832","DOI":"10.34133\/research.0832","article-title":"Emerging roles of GDF15 in metabolic and cardiovascular diseases","volume":"8","author":"Tian","year":"2025","journal-title":"Research"},{"key":"B6","doi-asserted-by":"publisher","first-page":"7","DOI":"10.2478\/raon-2020-0063","article-title":"Physical activity and cancer risk. 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