A team at the First Affiliated Hospital of Nanjing Medical University has published a study in the Journal of Translational Medicine in which the RFdiffusion protein design system generated, from scratch, a T-cell engager targeting CLDN18.2, offering a new approach to gastric cancer immunotherapy.
Key points:
AI de novo design of a binder: Rather than reusing a natural antibody scaffold, the team used the diffusion model RFdiffusion to "imagine" an entirely new protein binding surface out of nothing, and built a bispecific T-cell engager: one end grabs CLDN18.2 on the surface of gastric cancer cells, the other grabs CD3 on T cells, pulling killer cells next to the tumor. Selectivity tests showed it recognizes only CLDN18.2 and does not harm healthy lung epithelium that expresses the close relative CLDN18.1.
Multi-level experimental validation: From engineered cell lines, patient-derived tumor cells and patient organoids to immunocompetent mice and humanized mouse models, the molecule induced CLDN18.2-dependent tumor killing and activated CD8-positive T cells on every platform, showing that the AI-designed binder does not merely bind in a test tube but actually does the job.
The key twist is the microenvironment: In animal experiments the efficacy faded over time: cold tumors had few dendritic cells and their T cells showed exhaustion markers. After dendritic cells were added back, the IL-12 to CXCL9/CXCL10 signaling axis rebuilt a local immune circuit and the efficacy became durable. Mechanistic experiments showed that dendritic cells acted mainly as "cytokine factories" rather than antigen presenters.
Commentary: AI can design a perfect "bridge," but there must be soldiers at the other end. The study sets out a design principle for solid-tumor immunotherapy: AI-designed targeting molecules should be combined with strategies that rebuild the local immune microenvironment.
⚠️ This is a preclinical study (cell, organoid and mouse models) that has not entered human clinical trials; questions such as the source of the dendritic cells, their production and the timing of administration remain to be resolved.
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