Activation of the innate immune system counteracts tumor‐induced immunosuppression. Hence, small molecule‐based toll‐like receptor 7/8 agonists (TLR7/8a), which can modulate immunosuppression in the tumor microenvironment along with the activation of innate immunity, are emerging as essential components of cancer immunotherapy. However, the clinical application of synthetic TLR7/8a therapies is limited by systemic immune‐associated toxicity and immune tolerance induced by uncontrolled stimulatory activities and repeated treatments. To address these limitations, a dynamic immunomodulation strategy incorporating masking and temporal recovery of the activity of TLR7/8a through prodrug‐like TLR7/8a (pro‐TLR7/8a) at the molecular level and a sustained and controlled release of active TLR7/8a from nanoliposome (pro‐TLR7/8a) (NL(pro‐TLR7/8)) in a macroscale depot are designed. Immunization with cationic NL(pro‐TLR7/8) and anionic antigens triggers robust activation of innate immune cells as well as antigen‐specific T cell responses, eliciting reprogramming of immunosuppressive cells into tumor‐suppressive cells, with decreased systemic adverse effects and immune tolerance. Combination treatment with NL(pro‐TLR7/8a) and immune checkpoint inhibitors (anti‐CTLA‐4 plus anti‐PD‐L1) or nanoliposomes (Doxorubicin) has synergistic effects on antitumor immunity in various tumor models. The concept of pro‐TLR7/8a suggested herein may facilitate the advancement of small‐molecule‐based immunomodulators for clinical translation and safe and effective cancer immunotherapy.