NOD1/2 signaling in macrophages drives adaptive immune resistance in cancer.

Therapeutic resistance remains a prevalent and intractable clinical challenge across a broad spectrum of human malignancies. Despite extensive investigations, the intricate molecular networks by which the tumor microenvironment (TME) mediates such resistance are not fully understood. In this study, we identified nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) as pivotal regulators of adaptive resistance to diverse antitumor therapies, including immune checkpoint blockade (ICB), adoptive T-cell therapy, and cytotoxic chemotherapy. In murine tumor models, genetic ablation of NOD1/2 or receptor-interacting protein kinase 2 (RIPK2), as well as pharmacological inhibition of RIPK2, remodeled the TME by decreasing immunosuppressive macrophages and boosting CD8⁺ T cell infiltration and cytotoxicity. Mechanistically, NOD1/2 activation in macrophages upregulated programmed death-ligand 1 (PD-L1) expression via the RIPK2/NF-κB signaling axis, establishing an immunosuppressive TME that impaired CD8⁺ T cell-mediated antitumor immunity. Notably, in the clinically relevant setting of immunotherapy resistance, targeted suppression of NOD1/2 signaling in patient-derived peripheral blood mononuclear cells (PBMCs) restored and potentiated ICB responsiveness in patient-derived tumor organoids. Bioinformatic analyses further demonstrated that NOD1/2-associated gene signatures were significantly enriched in tumor-associated macrophages post-therapy. Our findings define NOD1/2 as a novel innate immune checkpoint that orchestrates therapy-induced adaptive resistance and highlight this pathway as a promising target to overcome treatment resistance in refractory cancers.