NOD1/2 signaling in macrophages drives adaptive immune resistance to diverse cancer therapies

Therapeutic resistance remains a critical challenge across many human malignancies, including lung cancer and castration-resistant prostate cancer. The tumor microenvironment (TME) often mediates this resistance, but the precise molecular networks are not fully understood. Current standard-of-care treatments, such as immune checkpoint blockade (ICB) and chemotherapy, frequently encounter limitations due to adaptive resistance mechanisms. Understanding these pathways, particularly those involving innate immune cells like macrophages, is crucial for developing novel strategies to overcome treatment failure and improve patient outcomes.

Researchers investigated the role of nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) in therapeutic resistance. They utilized murine tumor models, where genetic ablation of NOD1/2 or receptor-interacting protein kinase 2 (RIPK2) was performed. Additionally, pharmacological inhibition of RIPK2 was employed. The study also examined patient-derived peripheral blood mononuclear cells (PBMCs) and tumor organoids to assess ICB responsiveness. Key assays included flow cytometry (implied for immune cell analysis) and bioinformatic analyses of gene signatures.

The study identified NOD1/2 as pivotal regulators of adaptive resistance to diverse antitumor therapies, including ICB, adoptive T-cell therapy, and cytotoxic chemotherapy. In murine tumor models, genetic ablation of NOD1/2 or RIPK2, as well as pharmacological inhibition of RIPK2, significantly remodeled the TME. This remodeling resulted in decreased immunosuppressive macrophages and a boost in CD8⁺ T cell infiltration and cytotoxicity. Mechanistically, NOD1/2 activation in macrophages was found to upregulate programmed death-ligand 1 (PD-L1) expression. This occurred 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 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, reinforcing their role in resistance.