Nanomedicine, acting as the magic bullet, is capable of combining immunotherapy with other treatments to reverse a cold tumor (immune depletion) into a hot tumor. However, how to comprehensively inhibit the immunosuppressive tumor microenvironment (TME) remains a major challenge for immunotherapy to achieve the maximum benefits. Thus, a strategy that can simultaneously increase the recruitment of tumor infiltrating lymphocytes (TILs) and comprehensively reprogram the immunosuppressive TME is still urgently needed. Herein, a thermal-sensitive nitric oxide (NO) donor S-nitrosothiols (SNO)-pendant copolymer (poly­(acrylamide-co-acrylonitrile-co-vinylimidazole)-SNO copolymer, PAAV-SNO) with upper critical solution temperature (UCST) was synthesized and employed to fabricate an erythrocyte membrane-camouflaged nanobullet for codelivery of NIR II photothermal agent IR1061 and indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan (1-MT). This multifunctional nanobullet possessed long circulation in vivo, enhanced accumulation at the tumor site, and therapeutics-controlled release by NIR II laser, thereby it could avoid unspecific drug leakage while enhancing biosecurity. More importantly, the immunogenic cell death (ICD) induced by local hyperthermia from photothermal therapy (PTT) could be conducive for the increased recruitment of CD8+ cytotoxic T lymphocytes (CTLs) at the tumor site. Furthermore, through interfering in the IDO-1 activity by 1-MT and normalizing the tumor vessels by in situ generated NO, the immunosuppressive TME was comprehensively reprogrammed toward an immunostimulatory phenotype, achieving the excellent therapeutic efficacy against both primary breast cancer and metastases. Collectively, this multifunctional nanobullet described in this study developed an effective and promising strategy to comprehensively reprogram suppressive TME and treat “immune cold” tumors.

Combining chemo-therapeutics with immune checkpoint inhibitors facilitates killing cancer cells and activating the immune system through inhibiting immune escape. However, their treatment effects remain limited due to the compromised accumulation of both drugs and inhibitors in certain tumor tissues. Herein, a new poly (acrylamide- co -acrylonitrile- co -vinylimidazole- co -bis(2-methacryloyl) oxyethyl disulfide) (PAAVB) polymer-based intelligent platform with controllable upper critical solution temperature (UCST) was used for the simultaneous delivery of paclitaxel (PTX) and curcumin (CUR). Additionally, a hyaluronic acid (HA) layer was coated on the surface of PAAVB NPs to target the CD44-overexpressed tumor cells. The proposed nanomedicine demonstrated a gratifying accumulation in tumor tissue and uptake by cancer cells. Then, the acidic microenvironment and high level of glutathione (GSH) in cancer cells could spontaneously decrease the UCST of polymer, leading to the disassembly of the NPs and rapid drug release at body temperature without extra-stimuli. Significantly, the released PTX and CUR could induce the immunogenic cell death (ICD) to promote adaptive anti-tumor immunogenicity and inhibit immunosuppression through suppressing the activity of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme respectively. Therefore, the synergism of this intelligent nanomedicine can suppress primary breast tumor growth and inhibit their lung metastasis.

Hypoxia is a feature of solid tumors and it hinders the therapeutic efficacy of oxygen-dependent cancer treatment. Herein, we have developed all-organic oxygen-independent hybrid nanobullets ZPA@HA-ACVA-AZ for the “precise strike” of hypoxic tumors through the dual-targeting effects from surface-modified hyaluronic acid (HA) and hypoxia-dependent factor carbonic anhydrase IX (CA IX)-inhibitor acetazolamide (AZ). The core of nanobullets is the special zinc (II) phthalocyanine aggregates (ZPA) which could heat the tumor tissues upon 808-nm laser irradiation for photothermal therapy (PTT), along with the alkyl chain-functionalized thermally decomposable radical initiator ACVA-HDA on the side chain of HA for providing oxygen-independent alkyl radicals for ablating hypoxic cancer cells by thermodynamic therapy (TDT). The results provide important evidence that the combination of reverse hypoxia hallmarks CA IX as targets for inhibition by AZ and synergistic PTT/TDT possess incomparable therapeutic advantages over traditional (reactive oxygen species (ROS)-mediated) cancer treatment for suppressing the growth of both hypoxic tumors and their metastasis.

Imaging‐guided photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer treatment are beneficial for precise localization of the malignant lesions and combination of multiple cell killing mechanisms in eradicating stubborn thermal‐resistant cancer cells. However, overcoming the adverse impact of tumor hypoxia on PDT efficacy remains a challenge. Here, carrier‐free nano‐theranostic agents are developed (AIBME@IR780‐APM NPs) for magnetic resonance imaging (MRI)‐guided synergistic PTT/thermodynamic therapy (TDT). Two IR780 derivatives are synthesized as the subject of nanomedicine to confer the advantages for the nanomedicine, which are by feat of amphiphilic IR780‐PEG to enhance the sterical stability and reduce the risk from reticuloendothelial system uptake, and IR780‐ATU to chelate Mn2+ for T1‐weighted MRI. Dimethyl 2,2′‐azobis(2‐methylpropionate) (AIBME), acting as thermally decomposable radical initiators, are further introduced into nanosystems with the purpose of generating highly cytotoxic alkyl radicals upon PTT launched by IR780 under 808 nm laser irradiation. Therefore, the sequentially generated heat and alkyl radicals synergistically induce cell death via synergistic PTT/TDT, ignoring tumor hypoxia. Moreover, these carrier‐free nano‐theranostic agents present satisfactory biocompatibility, which could be employed as a powerful weapon to hit hypoxic tumors via MRI‐guided oxygen‐independent PTT and photonic TDT.