{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:01:19Z","timestamp":1785499279695,"version":"3.56.0"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"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>Physical activity has progressed from supportive care to an evidence-based oncologic intervention, with large cohort studies showing dose-dependent reductions in all-cause cancer mortality of roughly 20\u201347% across multiple tumor entities, and randomized trial evidence supporting a pooled reduction of approximately 26%. The CCTG CO.21 CHALLENGE trial, the first randomized controlled trial powered for survival endpoints, demonstrated that structured post-adjuvant exercise reduced disease recurrence by 28% and mortality by 37% in stage II\u2013III colon cancer survivors, with an effect size comparable to adjuvant chemotherapy. This narrative review proposes the Neuro-Immuno-Fascial (NIF) interface as a hypothetical integrative axis that may help explain how exercise influences tumor-related biology. Clinical trials have established that physical activity improves function, mitigates fatigue, and lowers recurrence risk in selected cohorts; however, the multi-step causal chain linking mechanical fascial remodeling to anti-tumor outcomes in humans remains speculative. Accordingly, the NIF construct is presented as a conceptual framework for translational research rather than a clinical decision-making tool. At the fascial\u2013stromal interface, preclinical data suggest that exercise-induced mechanical loading may activate Piezo1\/YAP\u2013TGF \u03b21 mechanotransduction cascades in cancer-associated fibroblasts and modulate immunosuppressive architecture via three convergent, yet exploratory, mechanisms: viscoelastic and hydration-driven remodeling of the extracellular matrix that may improve compliance and interstitial fluid dynamics; Piezo channel\u2013mediated mechanosensing that may influence myokine release (e.g., interleukin 6, irisin, SPARC) and associate with downstream changes in fibroblast behavior and natural killer cell trafficking; and autonomic rebalancing, reflected in 20\u201350% improvements in heart rate variability, which may attenuate pro-tumorigenic sympathetic tone. Direct human evidence that training-induced changes in fascial dynamics causally drive anti-tumor immunity is currently lacking. Preclinical findings further indicate that exercise-induced vascular normalization can increase tumor vessel perfusion and reduce hypoxia, although the magnitude and clinical relevance of these shifts in patients require further validation. On this basis, we outline three priorities for translational exercise oncology: standardized fascial and autonomic phenotyping using shear-wave elastography and heart rate variability spectral analysis; tumor microenvironment phenotype\u2013specific exercise dosing algorithms; and prospective trials combining aerobic and resistance training with myofascial interventions and immune checkpoint inhibition. Structured physical activity should remain a standard component of oncologic care, while NIF-informed phenotyping and dosing strategies warrant systematic investigation.<\/jats:p>","DOI":"10.3389\/fonc.2026.1894580","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T11:37:20Z","timestamp":1785497840000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Physical activity and the Neuro-Immuno-Fascial interface in cancer patients: mechanisms, clinical evidence, and therapeutic integration"],"prefix":"10.3389","volume":"16","author":[{"given":"Stephanie","family":"Otto","sequence":"first","affiliation":[{"name":"Comprehensive Cancer Center Ulm (CCCU), Ulm University Hospital","place":["Ulm, Germany"]},{"name":"Department of Gynaecology and Obstetrics, Ulm University Hospital","place":["Ulm, Germany"]},{"name":"Department of Internal Medicine I, Ulm University Hospital","place":["Ulm, Germany"]},{"name":"Department of Internal Medicine III, Ulm University Hospital","place":["Ulm, Germany"]},{"name":"Fascia Research Society (FRS)","place":["Burnsville, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An Thuy","family":"Ngo-Huang","sequence":"additional","affiliation":[{"name":"Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Klingler","sequence":"additional","affiliation":[{"name":"Fascia Research Group, Department of Neurosurgery, Ulm University Hospital","place":["Ulm, Germany"]},{"name":"Professorship for Conservative and Rehabilitative Orthopaedics, TUM School of Medicine and Health, Technical University Munich","place":["Munich, Germany"]},{"name":"Faculty of Health, Queensland University of Technology","place":["Brisbane, QLD, Australia"]},{"name":"Department of Anaesthesiology, Stiftung Rehabilitation Heidelberg (SRH) Hospital Sigmaringen","place":["Sigmaringen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/nrclinonc.2014.127","article-title":"Cancer-related fatigue--mechanisms, risk factors, and treatments","volume":"11","author":"Bower","year":"2014","journal-title":"Nat Rev Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2026.4996","article-title":"Longitudinal patterns of symptoms in patients undergoing chemotherapy: a secondary analysis of a cluster randomized clinical trial","volume":"9","author":"Paudel","year":"2026","journal-title":"JAMA Netw Open"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/01.ogx.0000480954.49941.b5","article-title":"Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society","volume":"314","author":"Oeffinger","year":"2015","journal-title":"Jama"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/sms.12581","article-title":"Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases","volume":"25","author":"Pedersen","year":"2015","journal-title":"Scandinavian J Med Sci Sports"},{"key":"B6","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1056\/nejmoa2502760","article-title":"Structured exercise after adjuvant chemotherapy for colon cancer","volume":"393","author":"Courneya","year":"2025","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2026.1741526","article-title":"Is there a link between fascia and cancer? 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