Uncoupling Type I Interferon Benefits From Inflammatory Toxicity: Transformer‐Prioritized Precision Agonists for Potent and Safer Cancer Immunotherapy

ABSTRACT Paclitaxel (PTX) chemotherapy is constrained by an “immunomodulatory paradox,” where antitumor Type I Interferon (IFN‐I) activation is coupled with detrimental pro‐inflammatory cascades. To address this challenge, we developed Deep Learning for Innate Immunity Modulatory Potential (DLINP), a Transformer‐based framework designed to identify precision immunomodulators that uncouple IFN‐I induction from deleterious inflammatory signaling. Screening 123 million entities identified Co68—an organometallic PNP‐pincer complex—as a dual‐functional agent with superior potency to conventional taxanes. In pancreatic ductal adenocarcinoma (PDAC) models, Co68 elicited robust antitumor responses that exceeded those of the gold‐standard STING agonist DMXAA. Single‐cell and spatial transcriptomics revealed that Co68 selectively re‐engineered the myeloid compartment, reprogramming tumor‐associated macrophages toward an interferon‐stimulated gene (ISG)‐high phenotype while quenching the pro‐inflammatory IL1β–PGE2 feedback loop. This reconfiguration converted “cold” tumor microenvironments into “hot” landscapes, enhancing NK and CD8 + T cell recruitment and synergy with anti–PD‐1 therapy. Mechanistically, Co68 engages the TLR4–MD2 complex via a non‐canonical binding mode, bifurcating innate signaling: triggering the TLR4–TRIF–IFN‐I axis while attenuating NF‐κB‐driven inflammation through an early, IFNAR‐independent TLR4–SYK–STAT1 pathway. Collectively, Co68 represents a taxane‐inspired precision therapeutic that uncouples beneficial antiviral‐like immunity from pathogenic inflammation, offering a transformative strategy for refractory solid tumors.