A Phase I clinical trial of an Fc-engineered CD40 agonist antibody (2141.V11), administered intratumorally, demonstrated remarkable systemic antitumor efficacy in metastatic cancer patients. Among 12 patients treated, six showed tumor shrinkage including two with complete remission in melanoma and breast cancer. Notably, responses extended beyond injected tumors, indicating a broad immune activation. This trial, led by Rockefeller University, offers promising avenues for safer, localized immunotherapy with systemic benefits in oncology.