Targeting Macrophage‐Mediated Lymphatic Immunosuppression to Prevent Tumor Recurrence After Microwave Ablation

Abstract

ABSTRACT Microwave ablation (MWA) is an effective locoregional therapy for solid tumors, but recurrence caused by minimal residual disease remains a clinical challenge. Although immunotherapy offers a strategy to prevent recurrence, the role of tumor‐draining lymph nodes (TDLNs) in post‐ablation immune regulation remains underexplored. Here, single‐cell RNA sequencing (scRNA‐seq) reveals pronounced macrophage remodeling in TDLNs following incomplete MWA (iMWA), characterized by an increased representation of immunosuppressive Folr2+ and Apoe+ macrophage subsets. These populations exhibit broad colony‐stimulating factor 1 receptor (Csf1r) expression, accompanied by enhanced CSF signaling and macrophage‐centered intercellular communication, implicating CSF1R‐associated macrophage remodeling in post‐ablation immunosuppression. Accordingly, an albumin‐based lipoprotein nanosystem co‐encapsulating paclitaxel (PTX) and the CSF1R inhibitor BLZ945 (PTX/BLZ945@Alb‐lip) was developed. Across multiple tumor models, PTX/BLZ945@Alb‐lip enhances immunomodulator delivery to both TDLNs and tumors, remodels the macrophage‐mediated immunosuppressive microenvironment, and suppresses residual tumor growth after iMWA. Moreover, treatment promotes durable antitumor immune memory and protects cured mice against tumor rechallenge. These findings identify TDLNs as an important therapeutic site in post‐ablation immunotherapy and provide a potential strategy to prevent tumor recurrence following ablation.