Targeted xCT‐mediated Ferroptosis and Protumoral Polarization of Macrophages Is Effective against HCC and Enhances the Efficacy of the Anti‐PD‐1/L1 Response

Abstract Tumor‐associated macrophages (TAMs) play an essential role in tumor progression, metastasis, and antitumor immunity. Ferroptosis has attracted extensive attention for its lethal effect on tumor cells, but the role of ferroptosis in TAMs and its impact on tumor progression have not been clearly defined. Using transgenic mouse models, this study determines that xCT‐specific knockout in macrophages is sufficient to limit tumorigenicity and metastasis in the mouse HCC models, achieved by reducing TAM recruitment and infiltration, inhibiting M2‐type polarization, and activating and enhancing ferroptosis activity within TAMs. The SOCS3‐STAT6‐PPAR‐ γ signaling may be a crucial pathway in macrophage phenotypic shifting, and activation of intracellular ferroptosis is associated with GPX4/RRM2 signaling regulation. Furthermore, that xCT‐mediated macrophage ferroptosis significantly increases PD‐L1 expression in macrophages and improves the antitumor efficacy of anti‐PD‐L1 therapy is unveiled. The constructed Man@pSiNPs‐erastin specifically targets macrophage ferroptosis and protumoral polarization and combining this treatment with anti‐PD‐L1 exerts substantial antitumor efficacy. xCT expression in tumor tissues, especially in CD68+ macrophages, can serve as a reliable factor to predict the prognosis of HCC patients. These findings provide further insight into targeting ferroptosis activation in TAMs and regulating TAM infiltration and functional expression to achieve precise tumor prevention and improve therapeutic efficacy.