Abstract Introduction: High-grade gliomas (HGG) are primary CNS tumors with poor prognosis. Cognitive impairment is highly prevalent at diagnosis, driven by tumor microenvironment, and amplified by treatment-related neurotoxicity. Evidence suggests that baseline cognitive deficits impair quality of life (QoL) and are associated with poor survival outcomes, yet limited options targeting this at diagnosis. In other populations, exercise and cognitive prehabilitation show neuroprotective effects. However, clinical justification for adoption in HGG is complicated by delays to treatment initiation, and aggressive disease progression. This narrative review aims to examine the rationale, therapeutic benefits, and feasibility of exercise and cognitive prehabilitation in HGG. Methods: A review was conducted to examine the role of exercise and cognitive prehabilitation in HGG. Articles (2015-present) were identified through targeted searches of PubMed and Embase using keywords including HGG, cognitive deficits, exercise, cognitive prehabilitation, and survival outcomes. Eligible studies included preclinical and clinical trials, observational studies, and peer-reviewed articles examining pathways, feasibility, and clinical significance of exercise, cognitive, or combined prehabilitation with respect to outcomes and QoL. Literature was synthesized qualitatively by two authors, with consensus reached through discussion, with an emphasis on translational relevance. Results: Evidence evaluating exercise, cognitive or combined prehabilitation in HGG remains scarce. Though, available preclinical and early clinical data support biological plausibility and translational relevance. Neuroinflammation and disrupted neuroplasticity are main contributors to cognitive deficits. Preclinical models reveal that physical exercise attenuates inflammatory signaling, enhancing immune surveillance, neurotrophic pathways, including BDNF expression, hippocampal neurogenesis, and synaptic plasticity. Cognitive training engages complementary activity-dependent plasticity and network compensation within vulnerable areas. Clinically, home-based, supervised exercise interventions have shown feasibility, safety, and acceptable adherence in clinically stable glioma patients, with modest improvements in physical fitness, cognitive performance, and PROs, though survival benefits have not yet been established. Given constraints in therapeutic timing, interventions may be flexibly integrated prior to treatment initiation, during perioperative, or alongside adjuvant therapy. Conclusion: Current evidence supports a strong biological rationale and clinical promise for exercise and cognitive prehabilitation in HGG, while the precision of implementation remains a critical constraint. Short, flexible, and low-burden interventions may be feasible within treatment windows for selected patients. Prospective trials are needed to define optimal timing, intensity, and patient selection, and to determine whether prehabilitation can meaningfully improve outcomes without compromising oncologic care. Citation Format: Minh Anh. Tran, Afsoon Moktar. Physical exercise and cognitive prehabilitation in high-grade glioma: A narrative review of mechanistic rationale, therapeutic benefits, and clinical constraints abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr B053.
Tran et al. (Mon,) studied this question.