CAR T cell-driven induction of iNOS in tumor-associated macrophages promotes CAR T cell resistance in B cell lymphoma

To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that the elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses.

CAR T cell-produced interferon-gamma (IFN-γ) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell functionality. Mechanistically, iNOS-expressing macrophages upregulated the p53 pathway, mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating the MYC pathway involved in ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle.