In Situ Vaccines in the Era of Cancer Immunotherapy: Conceptual Innovation and Clinical Translation

Historically, directly injecting therapeutics into tumors has been deemed suboptimal and less favorable in clinical settings compared to systemic administration due to the inability to eradicate circulating/metastatic tumor cells until the emergence of the concept of in situ vaccine. In situ vaccine leverages patients' own tumors as a pool of antigens to elicit systemic antitumor immunity (also known as "abscopal effect") that aims to eliminate both primary and distal/metastatic tumors. One typical example of an approved product is Talimogene laherparepvec, an oncolytic virus approved in 2015 for treating advanced melanoma. To improve the effectiveness and the biosafety of in situ vaccines, various approaches have emerged, including new generations of oncolytic viruses, engineered bacteria, cytokine treatment, immune adjuvants, nanotechnology-enabled formulations, and photo/radio-therapies, showing remarkable promise in preclinical and clinical settings. These conceptual advances offer tailored solutions to challenges such as low antigen availability, limited immune activation, and side effects. In this review, we explore the current landscape of in situ cancer vaccines, categorizing them based on their functional formulations and highlighting their conceptual innovation in cancer immunotherapy. Additionally, a comprehensive discussion is provided of the existing clinical trials and our perspective on future clinical translation.