Oral Immunotherapy Reshapes Intestinal Immunosuppression via Metabolic Reprogramming to Enhance Systemic Anti‐Tumor Immunity

Abstract Tumor immunotherapy offers a new paradigm to treat cancer; however, the existing regimens are accompanied by the dilemma of insufficient therapeutic outcomes and off‐target adverse effects. The intestinal immune system contains a bulk of immune cells, which can be important contributors to the maintenance of systemic immune homeostasis. However, manipulating intestinal immunity to achieve systemic anti‐tumor immunity is extremely challenging. Here, an oral immunotherapy strategy is reported using immune‐enhancing fullerenes (IEF) that can reinvigorate anti‐tumor immunity via immune cell‐metabolic reprogramming of intestinal immune cells. Findings show that IEF can remodel anti‐inflammatory macrophages into tumor‐killing macrophages by regulating the energy metabolism pathway from oxidative phosphorylation (OXPHOS) to glycolysis. Consequently, IEF can reprogram the immunosuppressive intestinal immunity and enhance sys temic immunity in vivo, thereby boosting anti‐tumor immunity and converting “cold” tumors into “hot” tumors. Oral immunotherapy strategy, modulating autoimmune cells in the intestine and achieving systemic anti‐tumor immunity, can ensure safe and efficient tumor immunotherapy.