Methods We report stimuli-responsive Toll-Like Receptor (TLR) agonist prodrugs that rely upon the irregular metabolism (Warburg Effect and efflux potential) common among different types of cancers to activate immune cells. Beginning with Coley’s Toxins in the late 1800’s, TLR agonists have exhibited anticancer properties, and more recently have been shown to act synergistically with anti-CTLA-4 or anti-PD-L1 checkpoint blockades. Specifically, TLR7/8 agonists deplete MDSCs, activate CD8+ T-cells, M1 macrophages and pDCs; and enhance abscopal effects across animal models for melanoma, breast, and prostate cancers. Despite these profound effects, the severe systemic inflammatory toxicity elicited by TLR agonists presents a significant barrier to using them as drugs. To address this, we developed stimuli-responsive TLR agonist prodrugs targeted to cancer cell metabolism. Results Our prodrugs are inactive until conversion by complementary stimuli selected from α-mannosidase, β-galactosidase, or β-glucuronidase with concomitant efflux via MDR1 and comparable processes. We observe conversion and efflux in several cancer types, including B16 melanoma, 4T1 breast, and TRAMP prostate cancers, resulting in immunogenicity as measured by activation of primary BMDCs. In-vivo, prodrugs do not induce systemic inflammation and perform differently than parent TLR agonist in a 4T1 neoadjuvant resection metastasis model. Conclusion These results suggest that stimuli-responsive TLR agonist prodrugs target the action of TLR agonists to cancer cell metabolism and mitigate systemic inflammatory effects relative to the parent TLR agonist.