Ultrasound‐generated antigens combined with TLR7/8 agonists as adjuvants have demonstrated significant anti‐tumor efficacy as an in‐situ vaccine. However, the use of TLR7/8 agonists can cause severe inflammatory responses. In this study, we present a novel tumor‐targeting nano‐adjuvant termed aPDL1‐PLG/R848 NPs, which are composed of aPDL1 antibody, Fc‐III‐4C peptide linker (Fc‐linker) and poly(_L‐glutamic acid)‐grafted‐R848. Under ultrasound irradiation, antigen‐presenting cells activate immune mechanisms in vivo under dual stimulation of in situ antigens and immune adjuvants. The strategy inhibits primary tumor growth and induces a strong antigen‐specific immune memory effect to prevent tumor recurrence in vivo. This work offers a safe and potent platform for an in situ cancer vaccine based on ultrasound therapy.

Reversing the hepatic inflammatory and immunosuppressive microenvironment caused by gut microbiota‐derived lipopolysaccharides (LPS), accumulating to the liver through the gut‐liver axis, is crucial for suppressing hepatocellular carcinoma (HCC) and metastasis. However, synergistically manipulating LPS‐induced inflammation and gut microbiota remains a daunting task. Herein, a Trojan‐horse strategy is proposed using an oral dextran‐carbenoxolone (DEX‐CBX) conjugate, which combines prebiotic and glycyrrhetinic acid (GA) homologs, to targeted delivery GA to HCC through the gut‐liver axis for simultaneous modulation of hepatic inflammation and gut microbiota. In the orthotopic HCC model, a 95–45% reduction in the relative abundances of LPS‐associated microbiota is observed, especially Helicobacter, caused by DEX‐CBX treatment over phosphate‐buffered saline (PBS) treatment. Notably, a dramatic increase (37‐fold over PBS) in the abundance of Akkermansia, which is known to strengthen systemic immune response, is detected. Furthermore, DEX‐CBX significantly increased natural killer T cells (5.7‐fold) and CD8⁺ T cells (3.9‐fold) as well as decreased M2 macrophages (59% reduction) over PBS treatment, resulting in a tumor suppression rate of 85.4%. DEX‐CBX is anticipated to offer a novel strategy to precisely modulate hepatic inflammation and the gut microbiota to address both the symptoms and root causes of LPS‐induced immunosuppression in HCC.