Reprogramming the tumor microenvironment from within: intratumoral immunoadjuvants in cancer immunotherapy

The immunosuppressive tumor microenvironment (TME) limits antigen presentation, immune trafficking, and therapeutic durability. Tumors range from immunoreactive microenvironments with pre-existing immune infiltration to immunosuppressive microenvironments characterized by myeloid-driven immunosuppression, dense stromal barriers, and effector T-cell exclusion. Intratumoral immunoadjuvants facilitate the transition of immunosuppressive TMEs toward immunoreactive states through activation of local innate immune signaling, chemokine-driven effector T-cell recruitment, and myeloid reprogramming, while amplifying pre-existing immunity in immunoreactive tumors. However, clinical translation is challenged by poor local retention and heterogeneous tumor architecture. This review integrates TME biology with advances in biomaterial-formulated delivery. Key immunoadjuvant classes, including STING, TLR, and RIG-I agonists, cytokines, and oncolytic viruses, are discussed with hydrogel depots, polymeric nanoparticles, and collagen-binding platforms that enhance retention and controlled release. Physical modulation through methods such as ultrasound and radiation is examined as a complementary approach to disrupt stromal barriers. A framework is proposed for matching immunoadjuvant class, biomaterial carrier, and dosing schedule to tumor-specific immunologic features that can drive lasting antitumor immunity.