Phosphines-Nitrogen-Phosphines Chelated CoCl2 Exhibits Potent Antitumor Activity in Pancreatic Cancer

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related deaths globally by 2030, yet effective therapeutic options remain limited. Within the pancreatic cancer tumor microenvironment (TME), tumor-associated macrophages (TAMs) secrete interleukin-1 beta (IL-1β), promoting cancer progression while suppressing type I interferons (IFN-I), which is critical for tumor killing. Utilizing the convolutional neural network (CNN)-based DLINP model developed in our laboratory, we identified Co68—an effective metal catalyst featuring a Phosphines-Nitrogen-Phosphines (PNP)-chelated CoCl₂ complex—as a promising candidate to modulate innate immune responses. In animal models of pancreatic cancer, Co68 demonstrated superior antitumor efficacy compared to the STING agonist DMXAA and showed enhanced therapeutic effects when combined with PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that Co68 reprogrammed TAMs to express interferon-stimulated genes (ISGs), attenuated pro-inflammatory cytokine secretion, and disrupted the IL-1β-PGE2 feedback loop, thereby facilitating the recruitment of NK and cytotoxic CD8⁺ T cells into the TME. Mechanistically, Co68 activated the IFN-I signaling pathway through the TLR4-TRIF-IFN-I axis and inhibited inflammation via the TLR4-SYK-STAT1 pathway. Collectively, these findings highlight the therapeutic potential of Co68, derived from PNP-pincer chemistry, to reshape immune dynamics within the pancreatic cancer TME, positioning it as a promising candidate for innovative immunotherapy strategies.