Regulating the regulators via targeting CD38 in the tumor microenvironment

TL;DR

This paper explores how targeting CD38 in the tumor microenvironment can help overcome immune suppression and improve cancer immunotherapy.

Contribution

The paper introduces CD38 as a multifaceted immunologic checkpoint and metabolic regulator in the tumor microenvironment.

Findings

CD38 promotes immune suppression by enhancing regulatory cell survival and metabolic fitness.

Targeting CD38 reverses immune suppression and restores effector T cell activity in tumors.

CD38 integrates with hypoxia-driven pathways to support immune evasion and therapeutic resistance.

Abstract

The immunosuppressive tumor microenvironment (TME) remains a major barrier to effective cancer immunotherapy. Among the central regulators of immune suppression, CD38, a multifunctional ectoenzyme and surface glycoprotein, has emerged as a pivotal orchestrator. CD38 is abundantly expressed on regulatory T cells (Tregs), regulatory B cells (Bregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs), where it enhances survival, metabolic fitness, and suppressive activity. Invariant natural killer T (iNKT) cells, which can either promote or suppress antitumor immunity, also express CD38 upon activation, suggesting a role for CD38 in directing their context-dependent fate within the TME. Mechanistically, CD38 regulates immune suppression through NAD+ hydrolysis, calcium signaling, and promotion of fatty acid oxidation (FAO) while impairing effector T-cell glycolysis and mitochondrial fitness under chronic hypoxia—conditions that favor exhaustion rather than enhanced cytotoxicity. By depleting extracellular NAD+, CD38 diminishes glycolysis and mitochondrial oxidative phosphorylation in effector T cells, while sustaining regulatory cell persistence through FAO. Its enzymatic products, cyclic ADP-ribose (cADPR) and NAADP, further mobilize calcium fluxes that reinforce suppressive function. CD38 also integrates with hypoxia-driven pathways; in CD38+ Bregs, stabilization of HIF-1α and induction of FAO-related genes such as CPT1A and PPARα/γ promote angiogenesis, immune-evasion, and therapeutic resistance. Therapeutically, targeting CD38 with monoclonal-antibodies, small-molecule inhibitors, or combinations with checkpoint blockade and macrophage-reprogramming agents has shown promise. Such interventions reverse immune suppression, restore effector T cell activity, and enhance tumor responsiveness to immunotherapy. In summary, CD38 functions as both a metabolic regulator and an immunologic checkpoint, coordinating suppressive networks and shaping iNKT cell fate. These multifaceted roles position CD38 as a transformative target for next-generation immunotherapies.

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