Engineered CAR-NK cells with tolerance to H2O2 and hypoxia can suppress postoperative relapse of triple-negative breast cancers

Abstract Surgical resection is a primary treatment option for triple-negative breast cancer (TNBC) patients, but it is associated with a high rate of postoperative local and metastatic relapse. Although chimeric antigen receptor–engineered natural killer (CAR-NK) cell therapy can specifically recognize and eradicate tumor cells, its therapeutic potency toward TNBCs is markedly suppressed by the hostile tumor microenvironment, which restricts the infiltration, survival and effector functions of CAR-NK cells inside the tumor masses. Herein, HER1-overexpressing TNBC-targeted CAR-NK (HER1-CAR-NK) cells were genetically engineered with catalase to endow them with tolerance toward the high levels of oxidative stress and hypoxia inside TNBC tumors through the catalytic decomposition of hydrogen peroxide, which is a principle reactive oxygen species inside tumors, into O2. We refer to these cells as HER1-CAR-CAT-NK cells. Upon intratumoral fixation with an injectable alginate hydrogel, HER1-CAR-CAT-NK cells enabled sustained tumor hypoxia attenuation and exhibited markedly enhanced persistence and effector functions inside TNBC tumors. As a result, locoregional HER1-CAR-CAT-NK cell therapy not only inhibited the growth of local primary residual tumors, but also elicited systemic antitumor activity to suppress the growth of distant tumors. This study highlights that genetic engineering of HER1-CAR-NK cells with catalase is a promising strategy to suppress the postoperative local and distant relapse of TNBC tumors.