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Cancer immunotherapy comprising of immune checkpoint blockade (ICB) therapy, immune cell therapies, cancer vaccines and many others represents a profound arsenal in the fight against different types of cancers. However, their overall clinical objective response rates, particularly against most solid tumors, are still not sufficient owing to a variety of reasons including the heterogenous expression of tumor antigens, limited tumor infiltration of effector immune cells, acquired tumor immunosuppression and some other factors. In recent years, various nanomedicine strategies have been proposed to assist cancer immunotherapy via distinct mechanisms, presenting new promises in many published studies. This perspective will thus provide a brief overview regarding the development of nanomedicine platforms for improving cancer immunotherapy.

TGF‐β signaling is a key player in tumor progression and immune evasion, and is associated with poor response to cancer immunotherapies. Here, we identified ubiquitin‐specific peptidase 8 (USP8) as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts both as a cancer stemness‐promoting factor and an activator of the TGF‐β/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF‐β receptor TβRII, leading to its increased expression in the plasma membrane and in tumor‐derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF‐β/SMAD‐induced epithelial‐mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TβRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF‐β/SMAD signaling, and reduces TβRII stability and the number of TβRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti‐tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy. Synopsis: TGF‐β signaling is a key factor in tumor progression and is associated with poor response to cancer immunotherapy. This work shows that pharmacologically targeting the deubiquitinase USP8 can antagonise TGF‐β/SMAD signalling and improve the efficacy of cancer immunotherapy USP8 is a metastasis enhancer that directly deubiquitinates and stabilises TGF‐β receptor TβRII, thereby promoting TGF‐β/SMAD signaling.Gain of USP8 function promotes the secretion of TβRII+ circulating extracellular vesicles that induce CD8+ T cell exhaustion.Pharmacological inhibition of USP8 represses TGF‐β signalling and inhibits cancer progression.USP8 inhibition alleviates CD8+ T cell exhaustion and improves the efficacy of breast cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has been demonstrated as a promising therapeutic strategy in clinic owing to its unique advantages. However, although more and more immunotherapeutic agents have been approved for clinical use to activate the immune system, they also could interfere with the homeostatic role of immune system at non-target sites after systemic administration, which may be associated with fatal side effects such as lifelong autoimmune diseases. Thus, it is desirable to develop local delivery systems that could be applied at the targeted sides and engineered to locally control the pharmacokinetics of various immunotherapeutics, including small molecules, macromolecules or even cells. Advancements in biomaterials, biotechnology, nanomedicine and engineering have facilitated the development of local delivery systems for enhanced cancer immunotherapy. This review will summarize the recent advances in developing different local delivery systems and discuss how these delivery systems could be designed to regulate the release behavior of different immunotherapeutics to sustainably stimulate the systemic immune system, effectively and safely inhibiting the cancer recurrence and metastasis. Furthermore, we will discuss how biomaterials-assisted local delivery systems would contribute to the development of cancer immunotherapy, together with their challenges and potential of clinical translation. Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract: Despite the remarkable progress in immune checkpoint blockade (ICB) therapy for cancer treatment, low objective response and immune‐related side effects (immune‐related adverse events, irAEs) limit the further development of ICBs. To address these challenges and enhance the efficiency of cancer immunotherapy, the emerging interest has focused on manipulating biomaterials to form innovational drug delivery systems that are necessary to effectively deliver immune checkpoint inhibitors. Such biomaterial‐based strategies can improve accumulation, control release, and enhance retention of checkpoint inhibitors within target locations while simultaneously reducing drug exposure for off‐target tissues, thereby optimizing both the efficacy and safety. In addition, with the assistance of biomaterials, combinations of ICB and conventional treatment strategies including chemotherapy, radiotherapy, and phototherapy are designed to further enhance the response rate of ICB. This review focuses on the latest reports on engineering biomaterials to improve the antitumor efficiency of ICB, with stress on antibody‐, gene‐, and trap protein–based immune checkpoint blockade strategies and their combinations with conventional therapies. Challenges and future trends in engineering biomaterials to modulate immune checkpoint therapy are discussed. [ABSTRACT FROM AUTHOR]

Unsatisfied cytoreductive surgery predicts worse clinical outcomes. Previous studies have found that cyclophosphamide (CTX) is a rhythmic immune modulator that can target suppressive regulatory immune cells and meanwhile enhance effector cells. Here, a therapeutic scaffold is engineered based on a fibrin hydrogel to codeliver CTX and anti‐PD‐L1 antibody (aPDL1) for the prevention of cancer recurrence postsurgery. It is demonstrated that the sequential release of CTX and aPDL1 from the fibrin hydrogel can lead to selective depletion of regulatory T cells (Treg) in the residual tumor, which would then synergize the immune checkpoint blockade therapy. The therapeutic benefit is demonstrated in an orthotopic breast tumor and an orthotopic ovarian tumor model after incomplete resection of primary tumors. In this work, the strategy provides a clinically valuable option for preventing cancer recurrence postsurgery. [ABSTRACT FROM AUTHOR]

Hydrogels, a class of materials with a 3D network structure, are widely used in various fields especially in biomedicine. Injectable hydrogels could facilitate the encapsulation and controlled release of small molecular drugs, macromolecular therapeutics, and even cells. With the rapid development of cancer immunotherapy, such injectable hydrogels have attracted wide attention for local immunomodulation to boost systemic anticancer immune responses, realizing more effective immunotherapy at lower doses. The latest progresses in the development of various smart injectable hydrogels for cancer immunotherapy are summarized here. Although applied locally, such injectable hydrogels can activate systemic antitumor immune responses, safely and effectively inhibiting the tumor metastasis and recurrence. Moreover, it is discussed how injectable hydrogel‐based cancer immunotherapy would contribute to the development of next generation of cancer treatment together with their potential for clinical translation. [ABSTRACT FROM AUTHOR]

Abstract Cancer vaccines for prevention and treatment of tumors have attracted tremendous interests as a type of cancer immunotherapy strategy. A major challenge in achieving robust T-cell responses to destruct tumor cells after vaccination is the abilities of antigen cross-presentation for antigen-presenting cells (APCs) such as dendritic cells (DCs). Herein, we demonstrate that a polyamidoamine dendrimer modified with guanidinobenzoic acid (DGBA) could serve as an effective protein carrier to enable delivery of protein antigen, thereby leading to effective antigen cross-presentation by DCs. With ovalbumin (OVA) as the model antigen and unmethylated cytosine-guanine dinucleotides (CpG) as the adjuvant, a unique type of tumor vaccine is formulated. Importantly, such DGBA-OVA-CpG nanovaccine can induce robust antigen-specific cellular immunities and further demonstrates outstanding prophylactic efficacy against B16-OVA melanoma. More significantly, the nanovaccine shows excellent therapeutic effect to treat established B16-OVA melanoma when used in combination with the programmed cell death protein 1 (PD-1) checkpoint-blockade immunotherapy. This study presents the great promises of employing rationally engineered cytosolic protein carriers for the development of tumor vaccines to achieve effective cancer immunotherapy. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Cancer local physical therapy (PT) by using heat, cold, electrical stimulation, irradiation or ultrasound to treat tumor is accepted as alternative choice for cancer patients. However, local recurrence and metastasis after such treatments remains to be the major cause of treatment failure and mortality. Therefore, it is necessary to develop a therapeutic strategy to inhibit local recurrence and metastasis. Inspired by the excellent inflammatory targeting ability of platelets, here we expect that the monoclonal antibody against programmed-death ligand 1 (aPDL1) engineered platelets could inhibit tumor local recurrence effectively, by facilitating transport of anti-PD-L1 antibodies to the ablated area with residue tumors. Using triple-negative breast carcinomas (4T1) bearing mouse model, we proved that antibody-coupled platelets could effectively target incompletely ablated tumor with thermal ablation (TA). We found the release of anti-PD-L1 can be triggered upon the platelets activation, together with many pro-inflammatory cytokines. The release of anti-PD-L1 is likely due to the dissociation of platelets upon the activation. Our findings approved that our platelet-based platform could facilitate the delivery of immune checkpoint antibody to tumor residues and remarkably prevent tumor recurrence after ablation. Moreover, this platelet-based delivery strategy may be extended to the targeted delivery of therapeutics post other types of local therapies including photodynamic therapy, high-intensity-focused-ultrasound ablation therapy, and even radiotherapy. Unlabelled Image [ABSTRACT FROM AUTHOR]

A variety of bioactive materials are currently developed to expand T cells ex vivo for adoptive T cell immunotherapy, also known as called artificial antigen-presenting cells (aAPCs). However, almost all the reported designs exhibit relatively smooth surface modified with T cell activating biomolecules, and therefore cannot well mimic the dendritic morphological characteristics of dendritic cells (DCs), the most important type of natural antigen-presenting cells (APCs) with high specific surface areas. Here, we propose a hydrophilic monomer-mediated surface morphology control strategy to synthesize biocompatible dendritic poly(N-isopropylacrylamide) (PNIPAM) microspheres for constructing aAPCs with surface morphology mimicking natural APCs (e.g., DCs). Interestingly, when maintaining the same ligands density, dendritic polymeric microspheres-based aAPCs (DPM beads) can more efficiently expand CD8+ T cells than that with smooth surfaces. Moreover, adoptive transfer of antigen-specific CD8+ T cells expanded by the DPM beads show significant antitumor effect of B16-OVA tumor bearing mice. Therefore, we provide a new concept for constructing biomimetic aAPCs with enhanced T cell expansion ability. [Display omitted] [ABSTRACT FROM AUTHOR]

The abnormal tumor vasculature is one of key reasons that lead to the limited tumor perfusion as well as hypoxic and immunosuppressive tumor microenvironment (TME). Herein, we uncover that by normalizing the tumor vasculature with erlotinib, a specific inhibitor of epidermal growth factor receptor (EGFR), the tumor perfusion and tumor oxygenation statuses in different types of tumors including murine breast tumors, colorectal tumors, and squamous cell carcinoma tumors, could be remarkably enhanced. As the results, the tumor uptake of drug-loaded nanoparticles as well as their interstitial penetration within the tumor would be greatly increased for mice pre-treated with erlotinib at the oral feeding dose of 50 mg/kg, leading to remarkably improved chemotherapeutic efficacy of nanomedicine. On the other hand, owing to the erlotinib-induced normalization of tumor vasculatures, the relieved hypoxic state in the three different types of tumors could alter the immunosuppressive TME into immunosupportive. Such an effect together with the increased tumor retention of anti-PDL1 antibody, a clinically approved checkpoint blockade agent, finally contributes to the greatly improved tumor inhibition effect in cancer immunotherapy. Therefore, our work presents a general yet effective strategy using a clinical drug to enhance the efficacies of cancer nanomedicine and immunotherapy by normalizing tumor vasculatures and modulating TME. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fluoroalkane-grafted polymers (F-PEI) based personalized mRNA cancer vaccine. • F-PEI promotes mRNA cellular delivery and activate the TLR4 pathway to activate DC. • No additional adjuvant is required in the F-PEI based mRNA cancer vaccine. • F-PEI/mRNA vaccine elicit MHC I antigen presentation and great anti-tumor immunity. • F-PEI/neoantigen mRNA vaccine can effectively prevent tumor reoccurrence. Messenger RNA (mRNA) vaccines, while demonstrating great successes in the fight against COVID-19, have been extensively studied in other areas such as personalized cancer immunotherapy based on tumor neoantigens. In addition to the design of mRNA sequences and modifications, the delivery carriers are also critical in the development of mRNA vaccines. In this work, we synthesized fluoroalkane-grafted polyethylenimine (F-PEI) for mRNA delivery. Such F-PEI could promote intracellular delivery of mRNA and activate the Toll-like receptor 4 (TLR4)-mediated signaling pathway. The nanovaccine formed by self-assembly of F-PEI and the tumor antigen-encoding mRNA, without additional adjuvants, could induce the maturation of dendritic cells (DCs) and trigger efficient antigen presentation, thereby eliciting anti-tumor immune responses. Using the mRNA encoding the model antigen ovalbumin (mRNAOVA), our F-PEI-based mRNAOVA cancer vaccine could delay the growth of established B16-OVA melanoma. When combined with immune checkpoint blockade therapy, the F-PEI-based MC38 neoantigen mRNA cancer vaccine was able to suppress established MC38 colon cancer and prevent tumor reoccurrence. Our work presents a new tool for mRNA delivery, promising not only for personalized cancer vaccines but also for other mRNA-based immunotherapies. [ABSTRACT FROM AUTHOR]

Vitamin C (VitC) has shown great promise to promote cancer immunotherapy, however, its high hydrophilicity makes it quickly excreted, leading to limited therapeutic efficiency even with frequent high-dose administration. Herein, we provide a pioneering report about the employment of VitC amphiphile self-assembled nanofiber hydrogels for enhanced cancer immunotherapy. Specifically, driven by hydrogen bonding and hydrophobic interactions, the synthesized VitC amphiphile, consisting of a hydrophilic VitC headgroup and a hydrophobic alkyl chain, could self-assemble into an injectable nanofiber hydrogel with self-healing properties. The formed VitC hydrogel not only serves as a reservoir for VitC but also acts as an effective delivery platform for stimulator of interferon genes (STING) agonist-4 (SA). Interestingly, the VitC hydrogel itself exhibits antitumor effects by upregulating genes related to interferon (IFN) signaling, apoptotic signaling and viral recognition and defense. Moreover, the SA-encapsulated VitC hydrogel (SA@VitC hydrogel) synergistically activated the immune system to inhibit the progression of both local and abscopal tumors. [ABSTRACT FROM AUTHOR]

As professional antigen presenting cells, dendritic cells (DCs) greatly determine the quality of the innate and adaptive immunities. Therefore, DC-based immunotherapy has been one of the hotspots in cancer immunotherapy in recent years. Although this unique therapeutic strategy has been approved by U.S. Food and Drug Administration for prostate cancer treatment, the efficacy of DC-based immunotherapy remains to be further improved. Moreover, it is still not completely clear about the immunological basis of DCs, which is another hurdle for the progress of DC-based immunotherapy. Due to their unique physicochemical properties, nanomaterials have shown potentials in addressing these above mentioned problems and have provided important guidelines for optimizing DC-based immunotherapy. However, it is still at the starting stage for this emerging field and there are many critical questions in the rational design of this therapeutic strategy to be answered. Therefore, it is greatly necessary to review and analyze recent progresses in this field. In this review, we mainly focus on the development of various types nanoparticles for DC-based immunotherapy. The existed challenges in this field are also discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] Cancer nanovaccines as one of immunotherapeutic approaches are able to attack tumors by stimulating tumor-specific immunological responses. However, there still exist multiple challenges to be tackled for cancer nanovaccines to evoke potent antitumor immunity. Particularly, the administration of exogenous materials may cause the off-target immunotherapy responses. In recent years, biomimetic nanovaccines by using cell lysates, cell-derived nanovesicles, or extracted cell membranes as the functional components have received extensive attention. Such nanovaccines based on cell-derived components would show many unique advantages including inherent biocompatibility and the ability to trigger immune responses against a range of tumor-associated antigens. In this review article, we will introduce the recent research progresses of those cell-derived biomimetic nanovaccines for cancer immunotherapy, and discuss the perspectives and challenges associated with the future clinical translation of these emerging vaccine platforms. [ABSTRACT FROM AUTHOR]

Tumor ablation therapies provide a minimally invasive approach to treat cancer. However, inhibition of cancer metastasis and recurrence after ablation is still a challenge in clinical trials. Here, we propose a strategy using combinatorial thermal ablation, adjuvants and immune checkpoint blockade (ICB) to inhibit metastatic tumor and recurrence via antitumor immune responses post tumor thermal ablation, which are frequently used in the clinic. Furthermore, a strong immune memory against cancer was observed 80 days after the primary tumor was ablated. Considering that all components in our design are approved by Food and Drug Administration (FDA), we provide a strategy based on clinically used cancer treatment technique that is promising in clinical translation. Image 1 [ABSTRACT FROM AUTHOR]