Conditions (23). These The evidence suggests that exercise training plays a crucial role

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2024 and 2025, spanning 3 journals. Those papers have been cited 36 times in total.

Supporting evidence — 3 representative gaps

• Exploring the Impact of Exercise-Derived Extracellular Vesicles in Cancer Biology (2024) · Biology · cited 3× · doi

  EV cargo can be considered a possible mechanism for the beneficial effects of exercise on cancer. The limited number of studies available in a relatively new area of exercise oncology precludes definitive conclusions from being drawn. To date, the results suggest a possible central role of EVs in spreading exercise-induced active molecules, such as proteins and ncRNAs, modulating a healthier global condition in cancer patients. By understanding and exploiting the specific profiles of EVs released during exercise, it might be possible to create future innovative therapeutic strategies based on exercise mimetics that deliver these benefits in vivo and/or identify specific molecular targets of drugs for new oncological therapies. Our knowledge in this field is still in its early stages, and many crucial questions remain unanswered. As a result, due to the speculative nature of exercise-derived EVs at this point, further in vitro and in vivo research is necessary. In vitro studies could provide insight into the intricate molecular and exercise-induced regulatory mechanisms that control the release of EVs and their role in regulating cancer cell behavior, including proliferation, apoptosis, and metastasis. These studies should also include the application of a 3D assay, co-culture systems, and/or the use of scaffold mimicking the extracellular matrix, as well as a focus on evaluating whether these EVs can enhance the effects of chemotherapy, radiation, or immunotherapy. These combination approaches could lead to more effective and less toxic treatment regimens. In vivo studies could explore the following: (1) how these EVs alter the immune landscape, potentially enhancing anti-tumor immunity or reducing immunosuppressive signals; (2) the optimal exercise regimen for producing beneficial EVs; (3) if the therapeutic effects of EVs are durable and if any long-term adverse effects emerge; and (4) the potential toxicity of administering these EVs. Finally, studies including patient-derived xenograft (PDX) models are recommended to understand the effects of exercise-derived EVs in a more clinically relevant context, potentially accelerating the translation of research into human trials. Author Contributions: Conceptualization, M.S. and I.D.; methodology, M.S. and I.D.; formal analysis, M.S. and I.D.; investigation, M.S. and I.D.; resources, I.D.; data curation, M.S. and I.D.; writing—original draft preparation, M.S. and I.D.; writing—review and editing, M.S., I.D., G.D., E.G. and P.S.; visualization, M.S. and I.D.; supervision, I.D.; project administration, I.D. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by PNR 2021-2027, DM n. 737 del 25-06-2021. Acknowledgments: We thank Daniela Caporossi for her suggestions and comments. Conflicts of Interest: The authors declare no conflicts of interest. Biology 2024, 13, 701

  generalfuture work
  Keywords: exercise effects possible cancer vivo derived beneficial role induced specific therapeutic molecular vitro including potentially
• Emerging Mechanisms of Physical Exercise Benefits in Adjuvant and Neoadjuvant Cancer Immunotherapy (2024) · Biomedicines · cited 12× · doi

  There is scientific evidence indicating that regular physical activity or exercise can have a positive impact on the immune system by promoting the mobilization of immune cells, potentially aiding their migration to tumors in the hours following each exercise session. Unlike immunotherapies, the immune benefits of exercise do not come with harmful side effects. Tailoring exercise programs to suit the individual characteristics of each patient can significantly improve their health status, including patients in advanced stages of cancer. Experts recommend that all individuals affected by cancer should engage in physical activity to the best of their ability. Further research is required to validate recent preclinical findings and explore the mechanisms through which exercise may prevent tumor formation Biomedicines 2024, 12, x FOR PEER REVIEW 9 of 15 Figure 1. A schematic representation of the effects of physical exercise. At baseline (the left part of the figure), cancer cells hinder the immune system through various mechanisms, promoting tu-mor burden (represented by the fire). Tumor metabolism induces hypoxia, which causes acidosis. This, in turn, reduces antigen presentation by releasing TGF-β and VEGF and the expression of PD-L1 by suppressor myeloid and tumor cells. Additionally, lactic acidosis reprograms the metabolic pathways of immune cells, inhibiting them [109]. Furthermore, elevated blood lactate and local nu-trient deprivation impair proper T cell autophagy, reducing their stemness and effector function [110]. In the tumor microenvironment, elevated ROS levels, arising from mitochondria and/or ex-ogenous sources, increase DNA damage and autophagy-mediated tumor cell survival and affect tumor immunity, promoting tumorigenesis [111,112]. Physical exercise can positively engage vari-ous mechanisms of the immune system to enhance anticancer therapies, particularly immunother-apies (the right part of the figure). Exercise-induced myokines (e.g., IL-6, IL-7, and IL-15) enhance immune cells, driving their recruitment and maturation at the tumor site [65–67]. Furthermore, ex-ercise training shifts the LDH isozyme profile, attenuating the lactate microenvironment in healthy and tumoral tissues [80]. During physical exercise, proper local oxygen concentration is restored, allowing skeletal muscles to drive lactate catalysis. The removal of lactate, in turn, restores immune cell metabolism and their functional capability [40,45–49,81–83,113]. 4. Conclusions and Future Directions There is scientific evidence indicating that regular physical activity or exercise can have a positive impact on the immune system by promoting the mobilization of immune cells, potentially aiding their migration to tumors in the hours following each exercise session. Unlike immunotherapies, the immune benefits of exercise do not come with harmful side effects. Tailoring exercise programs to suit the individual characteristics of each patient can significantly improv

  generalfuture work
  Keywords: exercise immune tumor physical cells system promoting lactate activity effects cancer mechanisms cell there scientific
• Exercise-induced adaptations in the kynurenine pathway: implications for health and disease management (2025) · Frontiers in Sports and Active Living · cited 21× · doi

  conditions (23). These The evidence suggests that exercise training plays a crucial role in in modulating KYN pathway metabolism, particularly individuals with chronic diseases characterized by low-grade inflammation drive KYN metabolism toward neurotoxic metabolites (12, 39), whereas toward the neuroprotective exercise training promotes a shift branch. This effect appears more pronounced in cancer patients due to elevated IDO activity, while findings in central nervous system disorders to methodological variations. Additionally, exercise volume and intensity seem to be key moderators of these benefits. inconsistent, possibly remain often due Despite promising results, few studies have explored exercise- induced KYN pathway adaptations in healthy adults. Additionally, most research has yet to establish direct links between KYN pathway changes and clinical outcomes (110). Future research should bridge this gap by integrating mechanistic insights with clinical relevance endpoints, particularly in metabolic, infectious, and cardiovascular including animal studies, could diseases. Experimental models, to help clarify dose-response provide controlled conditions relationship these pathways. Understanding mechanisms will enhance the therapeutic potential of exercise and refine its application in clinical settings. By addressing these challenges, future research can solidify the role of exercise in mitigating inflammation-driven neurotoxicity and advancing targeted interventions for vulnerable populations. underlying and Frontiers in Sports and Active Living 10 frontiersin.org Rangel et al. 10.3389/fspor.2025.1535152

  generalfuture work
  Keywords: exercise pathway clinical conditions training role metabolism particularly diseases ammation toward additionally future evidence suggests

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