Therapeutic Black Phosphorus Nanosheets Elicit Neutrophil Response for Enhanced Tumor Suppression

Abstract Black phosphorus (BP) has demonstrated potential as a drug carrier and photothermal agent in cancer therapy; however, its intrinsic functions in cancer treatment remain underexplored. This study investigates the immunomodulatory effects of polyethylene glycol‐functionalized BP (BP‐PEG) nanosheets in breast cancer models. Using immunocompetent mouse models‐including 4T1 orthotopic BALB/c mice and MMTV‐PyMT transgenic mice, it is found that BP‐PEG significantly inhibits tumor growth and metastasis without directly inducing cytotoxicity in tumor cells. Mass cytometry analysis reveals that BP‐PEG reshapes the tumor immune microenvironment by recruiting neutrophils. Neutrophil depletion experiments further demonstrate that the antitumor effects of BP‐PEG are dependent on neutrophils. Moreover, bulk and single‐cell RNA sequencing indicate that BP‐PEG is mainly taken up by macrophages, leading to the release of inflammatory factors such as IL1A and CXCL2, which enhance neutrophil recruitment and activation, thereby amplifying the antitumor immune response. Finally, co‐culture assays confirm that BP‐PEG indeed enhances the antitumor activity of neutrophils and natural killer (NK) cells. These findings position BP‐PEG as an immunomodulatory agent capable of reprogramming the tumor microenvironment to promote innate immunity against breast cancer. By stimulating neutrophil‐mediated antitumor activity, BP‐PEG offers a unique therapeutic approach that can potentially enhance the efficacy of existing cancer immunotherapies.