Ferroptosis is attracting significant attention due to its effectiveness in tumor treatment. The efficiency to produce toxic lipid peroxides (LPOs) at the tumor site plays a key role in ferroptosis. A hybrid PFP@Fe/Cu‐SS metal organic framework (MOF) is synthesized and shown to increase intratumoral LPO content through redox reactions generating ·OH. In addition, glutathione (GSH) depletion through disulfide‐thiol exchange leads to the inactivation of glutathione peroxide 4 (GPX4), which results in a further increase in LPO content. This MOF exhibits high inhibitory effect on the growth of xenografted Huh‐7 tumors in mice. The coadministration of a ferroptosis inhibitor reduces the antitumor effect of the MOF, leading to a restoration of GPX4 activity and an increase in tumor growth. Moreover, the construction of Cu into mesoporous PFP@Fe/Cu‐SS not only allows the MOF to be used as a contrast agent for T1‐weighted magnetic resonance imaging, but also renders its photothermal conversion capacity. Thus, near‐infrared irradiation is able to induce photothermal therapy and transform the encapsulated liquid perfluoropentane into microbubbles for ultrasound imaging.

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An ideal tumor treatment is supposed to eliminate the primary tumor and simultaneously trigger the host antitumor immune responses to prevent tumor recurrence and metastasis. Herein, a liposome encapsulating phosphoinositide 3-kinase gamma (PI3K ) inhibitor IPI-549 and photosensitizer chlorin e6 (Ce6), denoted by LIC, is prepared for colon cancer treatment. LIC internalized into CT26 cells generates reactive oxygen species (ROS) under laser irradiation to cause immunogenic tumor cell death, during which immunostimulatory signals such as calreticulin are released to further induce T lymphocyte-mediated tumor cell killing. Meanwhile, IPI-549 transported by liposome can inhibit PI3K in the myeloid-derived suppressive cells (MDSCs), resulting in downregulation of arginase 1 (Arg-1) and ROS to promote MDSCs apoptosis and reduce their immunosuppressive activity to CD8 + T cells. LIC-mediated immunogenic photodynamic therapy synergizes with MDSCstargeting immunotherapy, which significantly inhibits tumor growth via facilitating the dendritic cell maturation and tumor infiltration of CD8 + T cells while decreasing the tumor infiltration of immunosuppressive regulatory T cells, MDSCs, and M2-like tumor-associated macrophages. Moreover, the synergistic therapy increases the number of effector memory T cells (T EM ) in spleen, which suggests a favorable immune memory to prevent tumor recurrence and metastasis. The Ce6 and IPI-549-coloaded multifunctional nanodrug demonstrates high efficacy in colon cancer treatment.

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TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), also known as APO2L, belongs to the tumor necrosis factor family. By binding to the death receptor 4 (DR4) or DR5, TRAIL induces apoptosis of tumor cells without causing side toxicity in normal tissues. In recent years TRAIL-based therapy has attracted great attention for its promise of serving as a cancer drug candidate. However, the treatment efficacy of TRAIL protein was under expectation in the clinical trials because of the short half-life and the resistance of cancer cells. TRAIL gene transfection can produce a "bystander effect" of tumor cell killing and provide a potential solution to TRAIL-based cancer therapy. In this review we focus on TRAIL gene therapy and various design strategies of TRAIL DNA delivery including non-viral vectors and cell-based TRAIL therapy. In order to sensitize the tumor cells to TRAIL-induced apoptosis, combination therapy of TRAIL DNA with other drugs by the codelivery methods for yielding a synergistic antitumor efficacy is summarized. The opportunities and challenges of TRAIL-based gene delivery and therapy are discussed.

Nanotechnology-based photothermal therapy has attracted great attention in the past decade. Nevertheless, photothermal therapy has some inherent drawbacks, such as the uneven heat production and limited laser penetration, often leading to insufficient treatment outcomes. Here, we developed a combination strategy to improve cancer therapy. The biomimetic albumin-modified gold nanorods (AuNRs) were prepared with incorporation of paclitaxel (PTX). This therapeutic system was characterized by several features. First, the albumin modification enhanced the biocompatibility and colloidal stability. Second, the surface-coated albumin promoted cellular uptake via the albumin-binding protein pathway. Third, PTX was incorporated via hydrophobic interaction between PTX and the albumin lipophilic domain. Fourth, the system can be used for combined photothermo-chemotherapy for yielding synergistic effects. The antitumor activity of the system was evaluated both in vitro and in vivo using the HCT116 colon cancer cell and tumor model. The combination therapy was found with an enhanced treatment efficiency and no obvious side effect. Most importantly, the thermal effect was also discovered with the ability to modulate the tumor microenvironments and suppress the macrophages polarization towards the M2 pro-tumor phenotype. It could be a mechanism for photothermal immunotherapy. The combination strategy and the system provide a potential method for cancer therapy.

Recent breakthroughs in cell membrane-fabricated nanovaccine offer innovateive therapeutic options for preventing tumor metastasies and recurrence, yet the treatment of patient-specific solid tumor remained challenging owing to the immunosuppressive tumor microenvironment. Herein, we developed a personalized photothermal nanovaccine based on the surgical tumor-derived cell membranes (CMs) coating resiquimod (R848) loaded mesoporous polydopamine (MPDA) nanoparticles for targeting tumor photothermal immunotherapy and prevention. The fabricated photothermal nanovaccine MPDA-R848@CM (MR@C) demonstrates outstanding imaging-guided photothermal immunotherapy efficacy to eradicate solid tumors under near-IR laser irradiation and further inhibiting metastasis tumors by the resulted antitumor immunities, especially in combination with programmed death-ligand 1 antibody therapy (aPD-L1). Furthermore, from in vivo prophylactic testing results, it is confirmed that the 4T1 cells rechallenge can be prevented 100% in postsurgical tumor model after vaccination of the photothermal nanovaccine. Our work fabricates a personalized photothermal nanovaccine that possesses great potential for tumor-specific treatment and for preventing postoperative tumor recurrence.

renal cell carcinoma (RCC), [2] and nonsmall cell lung carcinoma (NSCLC). [3] Through active or passive means, tumor immunotherapy induces the body to produce a tumor-specific immune response which suppresses the tumor progression and prevents the tumor recurrence or metastasis. [4][5][6] Strategies reported for tumor immunotherapy so far mainly involved immune checkpoint blockade (ICB), [7] adoptive cell transfer therapy (ACT), [8] tumor-specific vaccines, [9] and application of small molecular immunemodulating drugs. [10] However, most immunotherapy methods often encounter the great challenge of not being effective enough for many tumors of which a large amount do not respond in the clinic, [11,12] requiring advanced tumor immunotherapy methods to be developed.Among various tumor immunotherapy strategies, inhibition of the indoleamine-2,3-dioxygenase (IDO) is drawing great attention at present because of its critical role in mediating tumor immune evasion, and some inspiring studies were reported. [13][14][15] Admittedly, IDO catalyzes the degradation of amino acid l-tryptophan (Trp) into the metabolite l-kynurenine (Kyn), which suppresses cytotoxic T lymphocytes (CTL) and activates regulatory T (Treg) cells. [16,17] The strong immunomodulatory functions of IDO can be attributed Immunotherapy brings great benefits for tumor therapy in clinical treatments but encounters the severe challenge of low response rate mainly because of the immunosuppressive tumor microenvironment. Multifunctional nanoplatforms integrating effective drug delivery and medical imaging offer tremendous potential for cancer treatment, which may play a critical role in combinational immunotherapy to overcome the immunosuppressive microenvironment for efficient tumor therapy. Here, a nanodrug (BMS-SNAP-MOF) is prepared using glutathione (GSH)-sensitive metal-organic framework (MOF) to encapsulate an immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) inhibitor BMS-986205, and the nitric oxide (NO) donor s-nitrosothiol groups. The high T1 relaxivity allows magnetic resonance imaging to monitor nanodrug distribution in vivo. After the nanodrug accumulation in tumor tissue via the EPR effect and subsequent internalization into tumor cells, the enriched GSH therein triggers cascade reactions with MOF, which disassembles the nanodrug to rapidly release the IDO-inhibitory BMS-986205 and produces abundant NO. Consequently, the IDO inhibitor and NO synergistically modulate the immunosuppressive tumor microenvironment with increase CD8 + T cells and reduce Treg cells to result in highly effective immunotherapy.In an animal study, treatment using this theranostic nanodrug achieves obvious regressions of both primary and distant 4T1 tumors, highlighting its application potential in advanced tumor immunotherapy.