Personalized Cancer Immunotherapy Boosted by cGAS‐STING‐Targeted Nanovaccines in Combination With Nutrient Modulation

Cyclic dinucleotides, which act as agonists for the stimulator of interferon genes (STING), are pivotal in stimulating both adaptive and innate immune reactions for advancing cancer immunotherapy. However, their therapeutic potential is hampered by inherent limitations, including susceptible degradation and inefficient delivery. Herein, we design genetically engineered bacteria (2'3'-cGAMP@<i>E.coli</i>) capable of producing 2'3'-cGAMP in the cytoplasm and then fabricate personalized nanovaccines (nECTs) by assembling 2'3'-cGAMP@<i>E.coli</i> with autologous tumor antigens instead of complicated chemical synthesis. Our in vitro analysis confirms that nECTs are capable of potently stimulating dendritic cell activity and amplifying the cross-presentation of antigens by leveraging the STING signaling route, underscoring their potential to bolster immune response priming. Translating these findings into in vivo models, vaccination with nECTs leads to a pronounced infiltration of effector T cells into tumor sites, concurrent with an IFN-β-mediated remodeling of the suppressive tumor microenvironment by innate immune cells. Notably, the therapeutic efficacy of nECTs is further augmented when coupled with a fasting-mimicking diet regimen, highlighting the synergistic potential of this combinatory strategy. Collectively, this dual modality represents a significant stride towards enhancing the precision and effectiveness of immunotherapeutic interventions in oncology.