CLEVER-1 blockade reprograms TAMs to overcome anti-PD-1 resistance in gastric cancer

Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) is a multifunctional scavenger receptor expressed on tumor-associated macrophages (TAMs). In a recent study published in the <i>Journal for ImmunoTherapy of Cancer</i>, Yu <i>et al</i> reported that CLEVER-1⁺ TAMs accumulate in advanced gastric cancer (GC), associate with poor prognosis, and contribute to resistance to chemoimmunotherapy. CLEVER-1 blockade using bexmarilimab reprogrammed TAMs toward a pro-inflammatory phenotype by suppressing peroxisome proliferator-activated receptor gamma (PPARγ)-driven lipid metabolism and enhancing antigen presentation and inflammatory cytokine secretion. CLEVER-1 blockade also synergized with anti-programmed cell death protein 1 (PD-1) therapy in ex vivo GC models, particularly in tumors enriched with CLEVER-1⁺ TAM. These findings identify CLEVER-1⁺ TAMs as both biomarker and functional mediator of anti-PD-1 therapy resistance, providing a rationale for combining bexmarilimab with immune checkpoint blockade in GC. In this commentary, we discuss the mechanistic significance, translational potential, and clinical prospects of CLEVER-1 blockade to overcome immunotherapy resistance in GC.