A first-in-human trial of an Fc-optimized CD40 agonistic antibody, 2141.V11, demonstrated promising systemic tumor regression in metastatic cancer patients. Delivered via intratumoral injection, six of twelve patients exhibited tumor shrinkage including two complete responses. The findings, published in Cancer Cell, highlight a novel immunotherapy approach activating tertiary lymphoid structures and systemic immune responses, offering new hope for advanced cancer treatment options.