Beyond borders: engineering organ-targeted immunotherapies to overcome site-specific barriers in cancer

Organ-targeted immunotherapy is emerging as a transformative strategy to significantly improve the precision, efficacy, and safety of cancer immunotherapy. Tumors frequently arise in, or metastasize to, immunologically unique organs such as the brain, liver, and lungs-each presenting formidable barriers that impede uniform treatment success. These organs not only represent common metastatic sites but also host distinct immune microenvironments that demand customized therapeutic approaches. Nanovaccine-based immunotherapies have recently gained traction as a promising solution to overcome these organ-specific challenges. The brain, protected by the blood-brain barrier (BBB), limits immune cell infiltration and drug penetration, especially in aggressive cancers like glioblastoma (GBM). The liver, characterized by its immune-tolerant landscape and dense population of phagocytic cells, suppresses antitumor responses in hepatocellular carcinoma (HCC). Meanwhile, the lungs' vast vasculature and continuous exposure to airborne antigens necessitate precision delivery strategies to trigger robust immunity without provoking excessive inflammation. To surmount these hurdles, nanocarriers have been engineered to leverage passive targeting through the enhanced permeability and retention (EPR) effect, active targeting via organ-specific ligands, immune cell hitchhiking, and stimuli-responsive release mechanisms. These innovations enable nanovaccines to elicit localized immune activation, reshape the tumor microenvironment (TME), and enhance cytotoxic T-cell responses. This review underscores the critical importance and urgent need for continued development of organ-specific nanovaccine platforms. It calls for intensified research efforts to translate these technologies into clinically viable therapies capable of addressing the most immunologically challenging tumor sites.