Photothermal therapy( PTT) is an extremely promising tumor therapeutic modality.H owever,e xcessive heat inevitably injures normal tissues near tumors,a nd the damage to cancer cells caused by mild hyperthermia is easily repaired by stress-induced heat shock proteins (HSPs). Thus, maximizing the PTT efficiency and minimizing the damage to healthy tissues simultaneously by adopting appropriate therapeutic temperatures is imperative.H erein, an innovative strategy is reported:f erroptosis-boosted mild PTT based on as ingle-atom nanozyme (SAzyme). The Pd SAzyme with atom-economical utilization of catalytic centers exhibits peroxidase (POD) and glutathione oxidase (GSHOx) mimicking activities,a nd photothermal conversion performance,w hich can result in ferroptosis featuring the up-regulation of lipid peroxides (LPO) and reactive oxygen species (ROS). The accumulation of LPO and ROSprovides apowerfulapproach for cleaving HSPs,which enables Pd SAzyme-mediated mildtemperature PTT.

The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu2MoS4 (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo‐dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu1+/2+, Mo4+/6+) exhibit Fenton‐like, glutathione (GSH) peroxidase‐like and catalase‐like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton‐like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase‐like CMS could react with endogenous H2O2 to generate O2 for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H2O2. The regenerated H2O2 can devote to Fenton‐like reaction for realizing GOx‐catalysis‐enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor‐killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O2−) generation performance. More importantly, the PEGylated CMS@GOx‐based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.

Despite the widespread applications of manganese oxide nanomaterials (MONs) in biomedicine, the intrinsic immunogenicity of MONs is still unclear. MnOx nanospikes (NSs) as tumor microenvironment (TME)‐responsive nanoadjuvants and immunogenic cell death (ICD) drugs are proposed for cancer nanovaccine‐based immunotherapy. MnOx NSs with large mesoporous structures show ultrahigh loading efficiencies for ovalbumin and tumor cell fragment. The combination of ICD via chemodynamic therapy and ferroptosis inductions, as well as antigen stimulations, presents a better synergistic immunopotentiation action. Furthermore, the obtained nanovaccines achieve TME‐responsive magnetic resonance/photoacoustic dual‐mode imaging contrasts, while effectively inhibiting primary/distal tumor growth and tumor metastasis.

Figure 3. a) Schematic illustration of the PTT-assisted immunotherapy. b) PD-L1 expression on 4T1 tumor cells after different treatments. c) Flow cytometric examination of the intratumor infiltration of CD4 + and CD8 + T cells. d,e) The primary and distal tumor growth curves of 4T1 tumor-bearing mice. f) Quantification of pulmonary metastasis nodules in different groups of 4T1 tumor-bearing mice. g) The tumor growth curves of B16F10-bearing mice model (*p < 0.05, **p < 0.01, ***p < 0.001). Reproduced with permission. [52] Copyright 2019, Nature Research.

No abstract

some immunotherapy approaches, such as immune checkpoint blockade (ICB) strategies, [1] adoptive T cell therapy (ACT), [2] and cancer vaccines have achieved significant clinical gains. [3] Regrettably, due to the intrinsic immunosuppressive TME, only a small proportion of patients can respond to immunotherapy. Therefore, how to reverse immunosuppressive TME is extremely urgent for sensitizing solid tumors to immunotherapy. The M2 phenotype tumor-associated macrophages (TAMs), a vital component of cell population within the TME, have long been recognized as a promoter of tumor growth and metastasis. [4] Fortunately, nanomaterials with ROS generation ability have exhibited remarkable TAMs regulatory functions to repolarize pro-tumoral M2 phenotype TAMs into tumoricidal M1 phenotype TAMs. [5] For example, Chen et al. fabricated mannose modified poly(lactic-co-glycolic acid) (PLGA) encapsulated indocyanine green and titanium dioxide photosensitizer, which successfully reprogrammed TAMs from pro-tumoral M2 phenotype to antitumor M1 phenotype via remarkable ROS generation. [6] Besides, Liu et al. constructed a Cu 2-x Te artificial enzyme with oxidative stress generating ability, which could effectively reverse immunosuppressive TME by skewing M2 phenotype TAMs into a pro-inflammatory M1 phenotype. [7] At present, some progress has been made in the field of cancer theranostics based on nanocatalysts (NCs), but achieving precise theranostics in response to the specific tumor microenvironment (TME) remains a major challenge. Herein, a TME-responsive upconversion nanoparticles (UCNPs)-based smart UCNPs@Cu-Cys-GOx (UCCG) nanosystem is engineered, which combines natural enzymes and nanozymes so as to amplify reactive oxygen species (ROS) generation in situ for cancer starvation/chemodynamic/immunotherapy. One of the biggest merits of this material is that it can be preserved inert (off) in normal tissues, and only in the TME can it be specifically activated (on) through a series of enzymatic cascades to boost ROS production via a strategy of open source (H 2 O 2 self-supplying ability) and reduce expenditure (glutathione (GSH) consuming ability). More importantly, the enhanced oxidative stress by UCCG NCs reverses the immunosuppressive TME, and facilitates antitumor immune responses. Meanwhile, the starvation/chemodynamic synergistic therapy triggered by UCCG combined with PD-L1 antibody effectively inhibits the growth of primary tumors and cancer metastasis. In addition, the UCNPs in UCCG present upconversion luminescence enhancement, which can be exploited to visualize the reinforced ROS generation in real time. Collectively, this work provides an original method for the devising and exploitation of UCNPs-based catalytic immunotherapy.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.202106010.

Rational design of tumor microenvironment (TME)‐activated nanocomposites provides an innovative strategy to construct responsive oncotherapy. In colorectal cancer (CRC), the specific physiological features are the overexpressed endogenous H2S and slightly acidic microenvironment. Here, a core–shell Cu2O@CaCO3 nanostructure for CRC “turn‐on” therapy is reported. With CaCO3 responsive to pH decomposition and Cu2O responsive to H2S sulfuration, Cu2O@CaCO3 can be triggered “on” into the therapeutic mode by the colorectal TME. When the CaCO3 shell decomposes and releases calcium in acidic colorectal TME, the loss of protection from the CaCO3 shell exposes the Cu2O core to be sulfuretted by H2S to form metabolizable Cu31S16 nanocrystals that gain remarkably strong near‐infrared absorption. After modifying hyaluronic acid, Cu2O@CaCO3 can achieve synergistic CRC‐targeted and TME‐triggered photothermal/photodynamic/chemodynamic/calcium‐overload‐mediated therapy. Moreover, it is found that the generation of hyperthermia and oxidative stress from Cu2O@CaCO3 nanocomposites can efficiently reprogram the macrophages from the M2 phenotype to the M1 phenotype and initiate a vaccine‐like immune effect after primary tumor removal, which further induces an immune‐favorable TME and intense immune responses for anti‐CD47 antibody to simultaneously inhibit CRC distant metastasis and recurrence by immunotherapy.

Upregulation of heat shock proteins (HSPs) drastically compromises the treatment effect of mild photothermal therapy (PTT). Herein, we designed a polyporous Cu single atom nanozyme (Cu SAzyme) loaded with licogliflozin (LIK066) for HSP-silencing induced mild PTT. On one hand, LIK066 inhibits glucose uptake by shutting sodium-dependent glucose transporter (SGLT) "valve", effectively blocking the energy source for adenosine triphosphate (ATP) generation. Without sufficient energy, cancer cells cannot synthesize HSPs. On the other hand, Cu SAzyme presents extraordinary multienzyme activities to induce reactive oxygen species (ROS) storm formation, which can damage the existing HSPs in cancer cells. Through a two-pronged strategy of SGLT inhibitor and ROS storm, LIK066-loaded Cu SAzyme shows high efficiency for comprehensive removal of HSPs to realize mild PTT.