Tumor Microenvironment Specific Regulation Ca-Fe-Nanospheres for Ferroptosis-Promoted Domino Synergistic Therapy and Tumor Immune Response.

Reactive oxygen species (ROS)-mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS-involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual-metal CaO2@CDs-Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca2+ upregulated and abundant H2O2 and O2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage-associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo.

Nanomaterials-Involved Tumor-Associated Macrophages' Reprogramming for Antitumor Therapy.

Tumor-associated macrophages (TAMs) play pivotal roles in tumor development. As primary contents of tumor environment (TME), TAMs secrete inflammation-related substances to regulate tumoral occurrence and development. There are two kinds of TAMs: the tumoricidal M1-like TAMs and protumoral M2-like TAMs. Reprogramming TAMs from immunosuppressive M2 to immunocompetent M1 phenotype is considered a feasible way to improve immunotherapeutic efficiency. Notably, nanomaterials show great potential for biomedical fields due to their controllable structures and properties. There are many types of nanomaterials that exhibit great regulatory activities for TAMs' reprogramming. In this review, the recent progress of nanomaterials-involved TAMs' reprogramming is comprehensively discussed. The various nanomaterials for TAMs' reprogramming and the reprogramming strategies are summarized and introduced. Additionally, the challenges and perspectives of TAMs' reprogramming for efficient therapy are discussed, aiming to provide inspiration for TAMs' regulator design and promote the development of TAMs-mediated immunotherapy.