Multifunctional immunotherapeutic gel prevented postoperative recurrence of hepatocellular carcinoma

[Display omitted] •Immunotherapeutic gel blocked MCSF-CSF-1R and CD47-SIRPα signal axes simultaneously.•Immunotherapeutic gel reduced stemness of tumor tissues by all trans retinoic acid.•Immunotherapeutic gel reshaped tumor microenvironment.•Immunotherapeutic gel inhibited postoperative tumor recurrence. Postoperative recurrence of hepatocellular carcinoma (HCC) remains an important cause of treatment failure. To mitigate the relapse of HCC, we have constructed an immunotherapeutic in situ fibrin gel to stimulate antitumor immune responses following HCC surgical resection. The gel consists of hollow mesoporous Prussian blue nanoparticles (HMPB) co-loaded with anti-SIRPα antibodies and the colony-stimulating factor 1 receptor (CSF-1R) small molecule inhibitor BLZ945, and differentiation inducer all-trans retinoic acid (ATRA). After the gel is formed in the surgical cavity, HMPB are released locally and then BLZ945 and anti-SIRPα antibody block the MCSF-CSF-1R and CD47-SIRPα signal axes respectively, which can repolarize tumor-associated macrophages (TAMs) from a tumorigenic M2 phenotype to an antitumor M1 phenotype, thus restoring their ability to kill cancer cells. In addition, ATRA released from the gel leads to the differentiation of cancer stem cells (CSCs) and increases their sensitivity to immunotherapy. Our findings indicate that this in situ immunotherapeutic gel can reshape the postoperative tumor microenvironment (TME) and induce antitumor responses, thereby inhibiting postoperative tumor recurrence.