PerC B‐Cells Activation via Thermogenetics‐Based CXCL12 Generator for Intraperitoneal Immunity Against Metastatic Disseminated Tumor Cells

Abstract

AbstractDuring cancer peritoneal metastasis (PM), conventional antigen‐presenting cells (dendritic cells, macrophages) promote tumorigenesis and immunosuppression in peritoneal cavity. While intraperitoneal immunotherapy (IPIT) has been used in clinical investigations to relieve PM, the limited knowledge of peritoneal immunocytes has hindered the development of therapeutic IPIT. Here, a dendritic cell‐independent, next‐generation IPIT is described that activates peritoneal cavity B (PerC B) cell subsets for intraperitoneal anti‐tumor immunity via exogenous antigen presentation. The PerC B‐cell‐involved IPIT framework consists of an isotropic‐porous, cell‐fitting, thermogenetics‐based CXCL12 generator. Such nanoscale thermal‐confined generator can programmatically fine‐tune the expression of CXCL12 to recruit disseminated tumor cells (DTCs) through CXCL12‐CXCR4 axis while avoiding cytokine storm, subsequently release DTC‐derived antigen to trigger PerC B‐cell‐involved immunity. Notably, antigen‐presenting B‐cell cluster, expressing the regulatory signaling molecules Ptpn6, Ms4a1, and Cd52, is identified playing the key role in the IPIT via single‐cell RNA sequencing. Moreover, such IPIT availably assuages peritoneal effusion and PM in an orthotopic gastric cancer and metastatic model. Overall, this work offers a perspective on PerC B‐cell‐involved antigen‐presenting in intraperitoneal immunity and provides a configurable strategy for activating anti‐DTC immunity for next‐generation IPIT.