血液系统恶性肿瘤中 T 细胞适应性的机制基础与治疗性调控以增强 CAR-T 细胞疗效

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.