In Situ Formed, Peritoneum‐Adhesive Immunogels Synergizing Low‐Dose Fractionated Radiotherapy Against Colorectal Peritoneal Carcinomatosis

Abstract

Immune checkpoint blockade (ICB) therapy holds great potentials for the treatment of colorectal peritoneal carcinomatosis (CRPC). However, its efficacy is often suboptimal due to the low immunogenic tumor phenotype, immunosuppressive tumor microenvironment (TME), and low antibody bioavailability at the peritoneal site. Herein, an in situ formed, anti‐cluster of differentiation 47 (aCD47) and anti–programmed cell death 1 ligand 1 (aPDL1) co‐loaded hydrogel (aCD47/aPDL1@PB–TA gel) with excellent peritoneum‐adhesive property and reactive oxygen species (ROS)‐responsive degradation is developed, bridging low‐dose fractionated radiotherapy (LDFRT) and ICB therapy for CRPC. The aCD47/aPDL1@PB‐TA gel is formed instantly upon mixing of the intraperitoneally injected, antibody‐containing solutions of phenylboronic acids‐containing polymer (PB) and tannic acid (TA), which can adhere to the peritoneum over 4 d. LDFRT promotes an immunogenic tumor phenotype by upregulating CD47 and PDL1, and reverses the immunosuppressive TME by fostering M1‐type macrophage polarization, dendritic cell maturation, and T cell infiltration. Moreover, LDFRT generates ROS to degrade the hydrogel and release the antibodies, consequently activating innate and adaptive immune responses. LDFRT and ICB therapy then cooperate to eliminate peritoneally metastasized CT26 colon tumor nodules in mice. Herein, a promising strategy is provided for LDFRT‐reinforced immunotherapy of CRPC, especially for patients with low immunogenic tumor.

Keywords

• colorectal peritoneal carcinomatosis
• immune checkpoint blockade
• in situ formed gel
• low-dose fractionated radiotherapy
• peritoneum adhesion