Naringin promotes cancer immunity by inducing cross-presentation by antigen-presenting cells

Successful immune checkpoint inhibitor (ICI) treatment of cancer requires adequate infiltration of cytotoxic CD8+T lymphocytes (CTLs) in tumors. Previous studies have identified the compound naringin, which increases CTL infiltration and rescues ICI efficacy in CTL-lacking tumors, and cancer CTL priming has been shown to rely on antigen cross-presentation (XPT). Therefore, the present study aimed to examine the effect of naringin on XPT by various human and murine antigen-presenting cells (APCs). The results indicated that naringin increases XPT by XPT-competent APCs, including murine bone marrow (BM) dendritic cells, peritoneal macrophages (MΦs), and human monocyte-derived dendritic cells (HMDCs). However, XPT was not observed with BM- or human monocyte-derived MΦs with or without naringin. Naringin reduced the activity of lysosomes, suppressing the degradation of internalized antigens, thereby increasing antigen cytosolic escape and MHC class I molecule-presenting antigens. In addition, human lymph node (LN) sinus MΦs were transcriptomically more similar to XPT-competent HMDCs than other LN MΦ groups. Taken together, these data suggest that naringin promotes XPT by XPT-competent APCs, which may explain why naringin was found to promote cancer immunity in our previous studies. This finding highlights the potential for developing cancer immunotherapies that induce XPT, offering a promising strategy to enhance antitumor immune responses.