Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment.

Tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as "living drugs," their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post-translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic-based strategies to enhance T cell immunotherapy.

Advances in promoting chimeric antigen receptor T cell trafficking and infiltration of solid tumors.

T cells engineered to express chimeric antigen receptors (CARs) have demonstrated robust response rates in treating hematological malignancies. However, solid tumors present multiple challenges that hinder the antitumor efficacy of CAR-T cells, including antigen heterogeneity, off-tumor and systemic toxicities, and the immunosuppressive milieu of the tumor microenvironment (TME). Notably, the TME of solid tumors is characterized by chemokine dysregulation and a dense architecture consisting of tumor stroma, extracellular matrix, and aberrant vasculature that impede migration of CAR-T cells to the tumor site as well as infiltration into the solid-tumor mass. In this review, we highlight recent advances to improve CAR-T-cell trafficking to and infiltration of solid tumors to promote effective antigen recognition by CAR-T cells.