Flexible manipulation of the fate of cancer cells through exogenous stimulation-induced metabolic reprogramming could handle the cellular plasticity-derived therapies resistance, which provides an effective paradigm for the treatment of refractory and relapsing tumors in clinical settings. Herein, we demonstrated that moderate heat (45 °C) could significantly regress the expression of antioxidants and trigger specific lipid metabolic reprogramming in cancer cells synergized with iron oxide nanoparticles (Fe 3 O 4 NPs). This metabolic control behavior destroyed the tumor redox homeostasis and produced overwhelming lipid peroxides, consequently sensitizing the tumor to ferroptosis. Based on these findings, a heat-triggered tumor-specific ferroptosis strategy was proposed by the rational design of a polypeptide-modified and 1H-perfluoropentane (1H-PFP)-encapsulated Fe 3 O 4 -containing nanoformulation (GBP@Fe 3 O 4 ). When irradiated by an 808 nm laser, the phase transition of 1H-PFP was triggered by localized moderate heat (45 °C), leading to burst release of Fe 3 O 4 in situ to produce potent reactive oxygen species through the Fenton reaction in the tumor microenvironment. Together with the antioxidant inhibition response and distinctive lipid metabolic reprogramming by heat stress, this oxidative damage was amplified to induce tumor ferroptosis and achieve sufficient antitumor effects. Importantly, we confirmed that ACSBG1, an acyl-CoA synthetase, was the key pro-ferroptotic factor in this heat-induced ferroptosis process. Moreover, knockout of this gene could realize cancer cell death fate conversion from ferroptosis to non-ferroptotic death. This work provides mechanistic insights and practical strategies for heat-triggered ferroptosis in situ to reduce the potential side effects of direct ferroptosis inducers and highlights the key factor in regulating cell fate under heat stress.

Immune responses stimulated by photodynamic therapy (PDT) and photothermal therapy (PTT) are a promising strategy for the treatment of advanced cancer. However, the antitumor efficacy by PDT or PTT alone is less potent and unsustainable against cancer metastasis and relapse. In this study, Gd 3+ and chlorin e6 loaded single‐walled carbon nanohorns (Gd‐Ce6@SWNHs) are developed, and it is demonstrated that they are a strong immune adjuvant, and have high tumor targeting and penetration efficiency. Then, three in vivo mouse cancer models are established, and it is found that sequential PDT and PTT using Gd‐Ce6@SWNHs synergistically promotes systemic antitumor immune responses, where PTT stimulates dendritic cells (DCs) to secrete IL‐6 and TNF‐ α , while PDT triggers upregulation of IFN‐ γ and CD80. Moreover, migration of Gd‐Ce6@SWNHs from the targeted tumors to tumor‐draining lymph nodes sustainably activates the DCs to generate a durable immune response, which eventually eliminates the distant metastases without using additional therapeutics. Gd‐Ce6@SWNHs intervened phototherapies also generate durable and long‐term memory immune responses to tolerate and prevent cancer rechallenge. Therefore, this study demonstrates that sequential PDT and PTT using Gd‐Ce6@SWNHs under moderate conditions elicits cooperative and long‐lasting antitumor immune responses, which are promising for the treatment of patients with advanced metastatic cancers.

Vaccines are powerful tools for controlling microbial infections and preventing epidemic diseases. Efficient inactive, subunit, or viral-like particle vaccines usually rely on a safe and potent adjuvant to boost the immune response to the antigen. After a slow start, over the last decade there has been increased developments on adjuvants for human vaccines. The development of adjuvants has paralleled our increased understanding of the molecular mechanisms for the pattern recognition receptor (PRR)-mediated activation of immune responses. Toll-like receptors (TLRs) are a group of PRRs that recognize microbial pathogens to initiate a host’s response to infection. Activation of TLRs triggers potent and immediate innate immune responses, which leads to subsequent adaptive immune responses. Therefore, these TLRs are ideal targets for the development of effective adjuvants. To date, TLR agonists such as monophosphoryl lipid A (MPL) and CpG-1018 have been formulated in licensed vaccines for their adjuvant activity, and other TLR agonists are being developed for this purpose. The COVID-19 pandemic has also accelerated clinical research of vaccines containing TLR agonist-based adjuvants. In this paper, we reviewed the agonists for TLR activation and the molecular mechanisms associated with the adjuvants’ effects on TLR activation, emphasizing recent advances in the development of TLR agonist-based vaccine adjuvants for infectious diseases.

GE11-PDA-Pt@USPIOs can relieve tumor hypoxic conditions efficiently and are highly effective for radio-chemotherapy of EGFR-positive tumors.

Tumor combination therapy using nano formulations with multimodal synergistic therapeutic effects shows great potential for complete ablation of tumors. However, targeting tumor metastases with nano structures is a major obstacle for therapy. Therefore, developing a combination therapy system able to target both primary tumors and their metastases at distant sites with synergistic therapy is desirable for the complete eradication of tumors. To this end, a dual chemodrug-loaded theranostic system based on single walled carbon nanohorns (SWNHs) is developed for targeting both primary breast tumors and their lung metastases.Methods: SWNHs were first modified simultaneously with poly (maleic anhydride-alt-1-octadecene) (C18PMH) and methoxypolyethyleneglycol-b-poly-D, L-lactide (mPEG-PLA) via hydrophobic-hydrophobic interactions and π-π stacking. Then cisplatin and doxorubicin (DOX) (2.9:1 molar ratio) were sequentially loaded onto the modified nanohorns in a noninterfering way. After careful examinations of the release profiles of the loaded drugs and the photothermal performance of the dual chemodrug-loaded SWNHs, termed SWNHs/C18PMH/mPEG-PLA-DOX-Pt, the dual drug chemotherapeutic and chemo-photothermal synergetic therapeutic effects on tumor cells were evaluated. Subsequently, the in vivo behavior and tumor accumulation of the drug-loaded SWNHs were studied by photoacoustic imaging (PAI). For chemo-photothermal therapy of tumors, 4T1 tumor bearing mice were intravenously injected with SWNHs/C18PMH/mPEG-PLA-DOX-Pt at a dose of 10 mg/kg b.w. (in SWNHs) and tumors were illuminated by an 808 nm laser (1W/cm2 for 5 min) 24 h post-injection.Results: DOX and cisplatin were loaded onto the modified SWNHs with high efficiency (44 wt% and 66 wt%, respectively) and released in a pH-sensitive, tandem and sustainable manner. The SWNHs/C18PMH/mPEG-PLA-DOX-Pt had a hydrodynamic diameter of 182 ± 3.2 nm, were highly stable in physiological environment, and had both dual drug chemotherapeutic (CI = 0.439) and chemo-photothermal synergistic antitumor effects (CI = 0.396) in vitro. Moreover, the dual drug-loaded SWNHs had a long blood half-life (10.9 h) and could address both the primary breast tumors and their lung metastases after intravenous administration. Consequently, chemo-photothermal combination therapy ablated the primary tumors and simultaneously eradicated the metastatic lung nodules.Conclusion: Our study demonstrates that SWNHs/C18PMH/mPEG-PLA-DOX-Pt is highly potent for chemo-photothermal combination therapy of primary tumors and cocktail chemotherapy of their metastases at a distant site.

Artificially modulating the type, density, and location of immune cells within the tumor microenvironment can suppress tumor growth and efficiently promote current immunotherapy. In this study, a magnetite nanoparticle‐based “immune‐guide” is developed by the functionalization of magnetite nanoparticles with hyaluronic acid (HA). HA, an extracellular matrix component, can target various CD44‐overexpressing tumors and mediate the adhesion and migration of multiple types of immune cells. Thus, HA‐functionalized magnetite nanoparticles (HA‐PDA@Fe3O4) can highly efficiently accumulate in breast cancer and penetrate deep into the tumor parenchyma. Consequently, high intratumoral concentration of HA, serving as a “guidepost,” can directly recruit lymphocytes and elicit more chemokine production through cascading amplification effects, turning the immune “cold” tumor into a “hot” one. More importantly, HA‐PDA@Fe3O4 can effectively remodel the diversity, origin, and activation of tumor‐associated macrophages by recruiting and activating infiltrating macrophages, while simultaneously reducing the M2‐maintained tissue‐resident macrophages. Thus, HA‐PDA@Fe3O4 synergistically improves T cell‐ and macrophage‐based immunotherapies as well as interferes with the formation of premetastatic niches in the lung. By redistributing the localization of HA in tumors by using magnetite nanoparticles, this study provides a unique strategy to modulate the tumor immune microenvironment and potentiate tumor immunotherapies by using biocompatible nanomaterials without any therapeutic drug.

In the past decade, we have witnessed the revolution in cancer therapy, especially in the rapid development of cancer immunotherapy. In particular, the introduction of nanomedicine has achieved great improvement in breaking the limitations of and immunological tolerance caused by clinic‐approved immunotherapies (cancer vaccine, CAR‐T, and immune checkpoint blockade) to enhance immunogenicity, antigen presentation and T lymphocyte infiltration for eradicating the primary tumors and distant metastases simultaneously. However, some fundamental but significant issues still need to be thoroughly clarified before the combination of nanomedicine and immunotherapy moves toward clinical translation such as biological safety and synergistic mechanisms of nanomaterials in the systematic immune responses. Therefore, in this review, the role of nanomaterials in cancer immunotherapy is summarized, mainly focusing on the effective activation and long‐term stimulation of both the innate and the adaptive immune responses and regulation of or remodeling the tumor microenvironment, especially the tumor immunosuppressive microenvironment. Also, we elaborate on the targets and challenges of nanomaterials in the cancer‐immunity cycle, summarize several main strategies to convert the cold tumor immune microenvironment to the hot one, and illustrate the progress in regulation of tumor immune microenvironment by targeting specific immunosuppressive cells. Finally, we prospect the nano‐combined immunotherapy strategies in tumor‐targeting, normalization of tumor immune environment and modification of macrophages. This article is characterized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Highlights MnO 2 @Ce6 nanoprobes-loaded-iPS cells (iPS-MnO 2 @Ce6) were developed for enhanced photodynamic and immunotherapy against cancer. Under the guidance of multi-mode real-time imaging, iPS-MnO 2 @Ce6 achieved an enhanced photodynamic therapeutic effect and stimulated a strong anti-tumor immune response in the tumor-bearing mouse. Abstract How to trigger strong anti-tumor immune responses has become a focus for tumor therapy. Here, we report the human-induced pluripotent stem cells (iPSs) to deliver MnO 2 @Ce6 nanoprobes into tumors for simultaneous photodynamic therapy (PDT) and enhanced immunotherapy. Ce6 photosensitizer was attached on manganese dioxide (MnO 2 ) nanoparticles, and resultant MnO 2 @Ce6 nanoprobes were delivered into mitomycin-treated iPSs to form iPS-MnO 2 @Ce6 nanoprobes. The iPS-MnO 2 @Ce6 actively targeted in vivo tumors, the acidic microenvironment triggered interaction between MnO 2 and H 2 O 2 , released large quantities of oxygen, alleviated hypoxia in tumor. Upon PDT, singlet oxygen formed, broken iPSs released tumor-shared antigens, which evoked an intensive innate and adaptive immune response against the tumor, improving dendritic cells matured, effector T cells, and natural killer cells were activated. Meanwhile, regulatory T cells were reduced, and then the immune response induced by iPS-MnO 2 @Ce6 was markedly stronger than the immune reaction induced by MnO 2 @Ce6 ( P < 0.05). The iPS-MnO 2 @Ce6 markedly inhibited tumor growth and metastasis and reduced mortality in mice models with tumor. Human iPSs loaded with MnO 2 -based nanoprobes are a promising strategy for simultaneous PDT and enhanced immunotherapy against tumor and own clinical translational prospect. Electronic supplementary material The online version of this article (10.1007/s40820-020-00452-y) contains supplementary material, which is available to authorized users.