Reinvigorating the Cancer-Immunity Cycle by Intratumoral Administration of Conventional Dendritic Cells in Melanoma...

Dendritic cells (DCs) are central to cancer immunity, orchestrating both innate and adaptive immune responses. In melanoma and other solid tumors, however, their function is often impaired within the tumor microenvironment (TME), leading to weakened antitumor immunity and diminished responses to immune checkpoint inhibitors (ICIs) and adoptive tumor-infiltrating lymphocyte (TIL) therapy. Among the various cell-based immunotherapy approaches, DC therapy-particularly using blood-derived conventional DCs (cDCs)-holds considerable promise. Compared with traditional monocyte-derived DCs (moDCs), cDCs exhibit superior antigen processing and cross-presentation capacities. The therapeutic application of cDCs was initially pioneered in vaccine strategies involving ex vivo antigen loading and maturation, followed by administration to lymph nodes. More recently, intratumoral (IT) cDC immunotherapy has emerged as a strategy to reinvigorate the cancer-immunity cycle by engaging the full repertoire of tumor-associated antigens while limiting systemic toxicity. This review discusses the underlying biological mechanisms and summarizes the clinical outcomes of IT DC therapy in cancer. Notably, combination approaches incorporating IT cDCs with ICIs, oncolytic viruses, synthetic adjuvants, radiation, or cryotherapy are emerging as promising strategies to overcome both primary and acquired resistance to ICI monotherapy. Collectively, these findings highlight the potential of integrating IT cDC therapy with complementary immunotherapies in next-generation, cross-tumor treatment strategies.