Mechanistic Basis and Therapeutic Modulation of T Cell Fitness to Enhance CAR-T Cell Efficacy in Hematological Malignancies

Karama Makni-Maalej^1,2Shaykhah Mujahhiz Alotaibi³Queenie Fernandes^1,2Syed Osman Ahmed³Sarra Mestiri⁴Salim Bougarn⁴Waad Amir⁴Syed Farhatullah³Mohamed Kharfan-Dabaja⁵Maysaloun Merhi^1,2Riad El Fakih³Mahmoud Aljurf^3*Said Dermime^1,2*

• ¹Hamad Medical Corporation, Doha, Qatar
• ²National Center for Cancer Care & Research, Doha, Qatar
• ³King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
• ⁴Hamad Bin Khalifa University Qatar Biomedical Research Institute, Doha, Qatar
• ⁵Mayo Clinic in Florida, Jacksonville, United States

T cell fitness has emerged as a critical determinant of the efficacy and persistence of Chimeric Antigen Receptor (CAR)-T cell therapy. Defined by the capacity of T cells to proliferate, resist exhaustion, persist in vivo, and exert sustained effector functions, T cell fitness reflects the integration of a dynamic network of intrinsic and extrinsic regulatory mechanisms. In this review, we present a comprehensive synthesis of the molecular and cellular foundations underlying T cell fitness, emphasizing the influence of differentiation trajectories, signaling pathways, metabolic reprogramming, and epigenetic modifications. We further discuss the impact of patient-specific conditions such as age as well as disease biology, prior therapeutic exposures, and timing and quality of T cell collection, on the phenotypic and functional efficacy of CAR-T cell products. Beyond delineating these determinants, we highlight emerging strategies aimed at enhancing T cell fitness. Importantly, we propose T cell fitness as an integrated, multi-layered systems property emerging from the interaction between differentiation state, signaling architecture, metabolic–mitochondrial competence, epigenetic stability, and host-specific inflammatory and treatment-related pressures. We introduce a mechanistic framework that links these layers across the CAR-T therapeutic timeline from leukapheresis to post-infusion tumor engagement and outline how this framework can be operationalized into measurable parameters to guide patient stratification, manufacturing decisions, and rational therapeutic interventions.