# Mechanistic basis and therapeutic modulation of T cell fitness to enhance CAR-T cell efficacy in hematological malignancies

## TL;DR

This paper reviews how T cell fitness impacts the success of CAR-T therapy and proposes strategies to improve it for better treatment outcomes in blood cancers.

## Contribution

The paper introduces a mechanistic framework linking T cell fitness to CAR-T efficacy across the treatment timeline.

## Key findings

- T cell fitness integrates differentiation, signaling, metabolism, and epigenetics to influence CAR-T outcomes.
- Patient-specific factors like age and prior treatments affect T cell quality and CAR-T performance.
- Strategies to enhance T cell fitness can guide manufacturing and therapeutic decisions.

## Abstract

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.

Infographic illustrating CAR-T cell therapy success factors, including optimal T-cell proliferative capacity, sustained T-cell effector function, and resistance to T-cell exhaustion, accompanied by graphics of T-cell proliferation, effector activity, and interaction with cancer cells. Additional panels show reduced T-cell senescence, less differentiated T-cell phenotype, and the optimal time for T-cell collection, with related diagrams of active T-cells, differentiation pathways, and blood draw.