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As a central intermediary between innate and adaptive immunity, CD40 activation engages dendritic cells (DCs), amplifies antigen presentation, and stimulates potent cytotoxic T\u2010cell (CTL) activity. Therapeutic CD40 agonists have been studied in a broad range of cancers over the past decade to reconfigure the tumor's immune microenvironment (TIME) and overcome immune refractoriness to standard immunotherapies. Clinical development has been most significant in pancreatic cancer, an exemplar cold tumor resistant to immune checkpoint blockade. Here, CD40 agonists have demonstrated efficacy to repolarize immune\u2010desert phenotypes to a more inflamed and treatable phenotype, particularly in combination with chemotherapy or programmed cell death protein 1 (PD\u20101) inhibitors. Clinical evidence has also been gained in melanoma and non\u2010small cell lung cancer, where CD40\u2010targeted strategies are examined in combination with current checkpoint inhibitors to accelerate T\u2010cell priming. In hematologic malignancies and B\u2010cell lymphomas, in particular, CD40 agonists exploit the natural activity of the B\u2010cell activating receptor, providing a strong biological rationale for their clinical efficacy. Exploratory studies have gone on to extend into bladder, prostate, mesothelioma, and head and neck cancers, demonstrating the broad translational relevance of this pathway. Hopes fostered by preliminary signs of activity remain to be qualified in light of the difficulties. Systemic immune activation\u2010associated toxicities, such as cytokine release syndrome, have justified cautious dosing schedules and exploration of local routes of drug administration. Additionally, heterogeneity between tumors in response underscores an urgent need for predictive biomarkers to enable the selection of patients and to tailor optimal clinical effects. In the future, drug development will be reliant on prudent combinations and novel delivery methods. Conjugation to vaccines, bispecific antibodies, radiotherapy, and oncolytic viruses is an attractive route to achieve their fullest immunostimulatory capabilities. Through a flexible approach to reeducate the immune microenvironment within tumors, CD40 agonist therapy can extend the use of immunotherapy to traditionally immune\u2010refractory malignancies. This review intends to present a cross\u2010cancer approach to CD40 agonist therapy, compiling existing clinical evidence while highlighting common issues and prospects for harnessing this pathway across various tumor settings.<\/jats:p>","DOI":"10.1002\/jbt.70675","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T18:03:56Z","timestamp":1767809036000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cross\u2010Cancer Perspectives on CD40 Agonist Therapy: Modulating the Tumor Immune Microenvironment"],"prefix":"10.1002","volume":"40","author":[{"given":"Xudong","family":"Hua","sequence":"first","affiliation":[{"name":"Dean's Office, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junyan","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Biochemical 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