Enhancing immunotherapy efficacy against MHC-I deficient triple-negative breast cancer using LCL161-loaded macrophage membranedecorated nanoparticles

Current cytotoxic T lymphocyte(CTL)activating immunotherapy requires a major histocompatibility complex I(MHC-I)-mediated presentation of tumor-associated antigens,which malfunctions in around half of patients with triple-negative breast cancer(TNBC).Here,we create a LCL161-loaded macrophage membrane decorated nanoparticle(LMN)for immunotherapy of MHC-I-deficient TNBC.SIRPa on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161,which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells.The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds.LMNs also block CD47-mediated phagocytosis suppression.LMNs inhibit the growth of MHC-I-deficient TNBC tumors,as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel,and prolong the survival of animals,during which process CTLs also play important roles.This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophagemediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.