Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy.

Chemotherapy and immune checkpoint inhibitors (ICIs) are widely utilized in cancer treatment, exerting not only direct cytotoxic effects on tumor cells but also significantly reshaping the systemic immune status of patients, particularly the composition and function of the T cell repertoire. This review begins with the analysis of the widespread depletion and dysfunction of early T cell subsets in cancer patients, particularly naïve T cells (Tn) and stem-like memory T cells (Tscm). Afterward, it details how chemotherapy and ICIs differentially regulate T cell homeostasis, including their ability to induce T cell exhaustion and differentiation skewing, as well as their ability to stimulate immunity and remodel the tumor microenvironment. On this basis, it is shown that the quality of T cell memory phenotypes is central in determining the in vivo expansion and persistence of chimeric antigen receptor T (CAR-T) cells. To overcome the challenges of classical autologous CAR-T therapy, which stems from raw material quality and in vitro manufacturing bottlenecks, we focus on transforming chemotherapy and ICIs from traditional treatment modalities into beneficial "host preconditioning" regimens aimed at optimizing the baseline state of the endogenous T cell repertoire. All in all, this transformation of traditional therapies into host preconditioning strategies, along with recent advances in in vivo CAR-T approaches, provides theoretical grounds and translatable clues to develop next-generation cellular immunotherapy.