Tumor-associated macrophages (TAMs) of M2 phenotype have mediated the 
immunosuppression in a tumor microenvironment, facilitating the escape of tumor 
cells from immunosurveillance. Reprograming the immunosuppressive M2 TAMs to 
immunostimulatory M1 phenotype can activate the antitumor immune responses for 
cancer immunotherapy. Herein, hollow iron oxide (Fe3O4) nanoparticles (NPs) were 
employed to reprogram M2 TAMs toward M1 TAMs, aiming to release proinflammatory 
cytokines and recruit T cells to kill tumor cells. After loaded with l-arginine 
(l-Arg) and sealed with poly(acrylic acid) (PAA), hollow Fe3O4 NPs were 
fabricated into LPFe3O4 NPs, which could release l-Arg based on pH-responsive 
PAA and produce nitric oxide (NO) with the help of nitric oxide synthase (iNOS) 
overexpressed by M1 TAMs, as a result of additional tumor elimination for gas 
therapy. In vitro and in vivo studies demonstrate that LPFe3O4 NPs could 
effectively reprogram M2 to M1 macrophages, activating T cells, releasing TNF-α, 
and producing high levels of NO, leading to synergistic tumor therapy.