Exosomal NGFR derived from gastric cancer drives PANoptosis of M2 macrophages by activating RIPK1 via phosphorylation

Gastric cancer (GC) is the fifth most common cancer with a high mortality rate. Exploration of therapeutic targets to develop effective strategies for GC treatment is urgent. Nerve growth factor receptor (NGFR) exerts inhibitory effects on GC by modulating the tumor microenvironment (TME). However, the role of NGFR in M2 macrophages is largely unknown. M2 polarization of macrophages was conducted by treating PMA-incubated THP-1 cells with interleukin 4 (IL4) and IL13 and identified via flow cytometric analysis. Exosomes derived from GC cells were isolated and utilized to incubate M2 macrophages. Protein-protein interaction was determined using coimmunoprecipitation (Co-IP). NGFR of GC cells triggers PANoptosis of M2 macrophages. Mechanism investigation indicates that NGFR of GC cells facilitates PANoptosis of M2 macrophages by exosomes. Moreover, NGFR binds with RIPK1 to phosphorylate receptor-interacting serine/threonine-protein kinase 1 (RIPK1) at Ser161 and 166 in M2 macrophages, and NGFR induces PANoptosis of M2 macrophages by activating RIPK1. This study indicates that exosomal NGFR derived from GC drives PANoptosis of M2 macrophages by activating RIPK1 via phosphorylation. Our findings not only highlight the inhibitory effect of GC-derived NGFR on TME but also provide novel targets and strategies for GC treatment.