A novel Fc-optimized CD40 agonistic antibody demonstrated promising antitumor activity in a Phase I trial involving 12 metastatic cancer patients. Administered via intratumoral injection, the antibody triggered systemic immune responses, leading to tumor shrinkage both at treated sites and distant locations. Remarkably, two patients exhibited complete remission. These findings, published in Cancer Cell, suggest a potential new immunotherapy avenue for advanced cancers, addressing prior challenges with systemic toxicity encountered by CD40 agonists.