Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment.

Osteosarcoma, a malignant bone tumor often characterized by high hedgehog signaling activity, residual tumor cells, and substantial bone defects, poses significant challenges to both treatment response and postsurgical recovery. Here, we developed a nanocomposite hydrogel for the sustained co-delivery of bioactive magnesium ions, anti-PD-L1 antibody (αPD-L1), and hedgehog pathway antagonist vismodegib, to eradicate residual tumor cells while promoting bone regeneration post-surgery. In a mouse model of tibia osteosarcoma, this hydrogel-mediated combination therapy led to remarkable tumor growth inhibition and hence increased animal survival by enhancing the activity of tumor-suppressed CD8+ T cells. Meanwhile, the implanted hydrogel improved the microenvironment of osteogenesis through long-term sustained release of Mg2+, facilitating bone defect repair by upregulating the expression of osteogenic genes. After 21 days, the expression levels of ALP, COL1, RUNX2, and BGLAP in the Vis-αPD-L1-Gel group were approximately 4.1, 5.1, 5.5, and 3.4 times higher than those of the control, respectively. We believe that this hydrogel-based combination therapy offers a potentially valuable strategy for treating osteosarcoma and addressing the tumor-related complex bone diseases.

Responsive and traceless assembly of iron nanoparticles and 131I labeled radiopharmaceuticals for ferroptosis enhanced radio-immunotherapy.

Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.

A carrier-free nanovaccine combined with cancer immunotherapy overcomes gemcitabine resistance.

Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.

Liposomes-enabled cancer chemoimmunotherapy.

Chemoimmunotherapy is an emerging paradigm in the clinic for treating several malignant diseases, such as non-small cell lung cancer, breast cancer, and large B-cell lymphoma. However, the efficacy of this strategy is still restricted by serious adverse events and a high therapeutic termination rate, presumably due to the lack of tumor-targeted distribution of both chemotherapeutic and immunotherapeutic agents. Targeted drug delivery has the potential to address this issue. Among the most promising nanocarriers in clinical translation, liposomes have drawn great attention in cancer chemoimmunotherapy in recent years. Liposomes-enabled cancer chemoimmunotherapy has made significant progress in clinics, with impressive therapeutic outcomes. This review summarizes the latest preclinical and clinical progress in liposome-enabled cancer chemoimmunotherapy and discusses the challenges and future directions of this field.

Napabucasin deactivates STAT3 and promotes mitoxantrone-mediated cGAS-STING activation for hepatocellular carcinoma chemo-immunotherapy.

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

An ultra-long-acting L-asparaginase synergizes with an immune checkpoint inhibitor in starvation-immunotherapy of metastatic solid tumors.

Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.

Manganese-coordinated nanoparticle with high drug-loading capacity and synergistic photo-/immuno-therapy for cancer treatments.

Stimulator of interferon genes (STING) agonists have shown promise in cancer treatment by stimulating the innate immune response, yet their clinical potential has been limited by inefficient cytosolic entry and unsatisfactory pharmacological activities. Moreover, aggressive tumors with "cold" and immunosuppressive microenvironments may not be effectively suppressed solely through innate immunotherapy. Herein, we propose a multifaceted immunostimulating nanoparticle (Mn-MC NP), which integrates manganese II (Mn2+) coordinated photosensitizers (chlorin e6, Ce6) and STING agonists (MSA-2) within a PEGylated nanostructure. In Mn-MC NPs, Ce6 exerts potent phototherapeutic effects, facilitating tumor ablation and inducing immunogenic cell death to elicit robust adaptive antitumor immunity. MSA-2 activates the STING pathway powered by Mn2+, thereby promoting innate antitumor immunity. The Mn-MC NPs feature a high drug-loading capacity (63.42 %) and directly ablate tumor tissue while synergistically boosting both adaptive and innate immune responses. In subsutaneous tumor mouse models, the Mn-MC NPs exhibit remarkable efficacy in not only eradicating primary tumors but also impeding the progression of distal and metastatic tumors through synergistic immunotherapy. Additionally, they contribute to preventing tumor recurrence by fostering long-term immunological memory. Our multifaceted immunostimulating nanoparticle holds significant potential for overcoming limitations associated with insufficient antitumor immunity and ineffective cancer treatment.

A natural adhesive-based nanomedicine initiates photothermal-directed in situ immunotherapy with durability and maintenance.

Tumor immunotherapies have emerged as a promising frontier in the realm of cancer treatment. However, challenges persist in achieving localized, durable immunostimulation while counteracting the tumor's immunosuppressive environment. Here, we develop a natural mussel foot protein-based nanomedicine with spatiotemporal control for tumor immunotherapy. In this nanomedicine, an immunoadjuvant prodrug and a photosensitizer are integrated, which is driven by their dynamic bonding and non-covalent assembling with the protein carrier. Harnessing the protein carrier's bioadhesion, this nanomedicine achieves a drug co-delivery with spatiotemporal precision, by which it not only promotes tumor photothermal ablation but also broadens tumor antigen repertoire, facilitating in situ immunotherapy with durability and maintenance. This nanomedicine also modulates the tumor microenvironment to overcome immunosuppression, thereby amplifying antitumor responses against tumor progression. Our strategy underscores a mussel foot protein-derived design philosophy of drug delivery aimed at refining combinatorial immunotherapy, offering insights into leveraging natural proteins for cancer treatment.

Orchestrated metal-coordinated carrier-free celastrol hydrogel intensifies T cell activation and regulates response to immune checkpoint blockade for synergistic chemo-immunotherapy.

The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.

Evaluating the Efficacy of Immune Checkpoint Inhibitors in Elderly Patients: A Systematic Review and Meta-analysis.

In this chapter, we outline the steps for designing and conducting a rigorous systematic review and meta-analysis, focusing on the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. ICIs have improved survival rates in advanced cancers, yet their effectiveness in older populations remains unclear. We detail the essential processes involved in both systematic reviews and meta-analyses. We can evaluate the efficacy of ICIs in elderly patients with advanced cancer, examining outcomes such as overall survival and progression-free survival.

Targeted nanoprobe for magnetic resonance imaging-guided enhanced antitumor via synergetic photothermal/immunotherapy.

Synergistic photothermal/immunotherapy has garnered significant attention for its potential to enhance tumor therapeutic outcomes. However, the fabrication of an intelligent system with a simple composition that simultaneously exerts photothermal/immunotherapy effect and imaging guidance function still remains a challenge. Herein, a glutathione (GSH)-responsive theranostic nanoprobe, named HA-MnO2/ICG, was elaborately constructed by loading photothermal agent (PTA) indocyanine green (ICG) onto the surface of hyaluronic acid (HA)-modified manganese dioxide nanosheets (HA-MnO2) for magnetic resonance (MR) imaging-guided synergetic photothermal/immuno-enhanced therapy. In this strategy, HA-MnO2 nanosheets were triggered by the endogenous GSH in tumor microenvironment to generate Mn2+ for MR imaging, where the longitudinal relaxation rate of HA-MnO2/ICG was up to 14.97 mM-1s-1 (∼24 times than that found in a natural environment), demonstrating excellent intratumoral MR imaging. Moreover, the HA-MnO2/ICG nanoprobe demonstrates remarkable photothermal therapy (PTT) efficacy, generating sufficient heat to induce immunogenic cell death (ICD) within tumor cells. Meanwhile the released Mn2+ ions from the nanosheets function as potent immune adjuvants, amplifying the immune response against cancer. In vivo experiments validated that HA-MnO2/ICG-mediated PTT was highly effective in eradicating primary tumors, while simultaneously enhancing immunogenicity to prevent the growth of distal metastasis. This hybrid HA-MnO2/ICG nanoprobe opened new avenues in the design of MR imaging-monitored PTT/immuno-enhanced synergistic therapy for advanced cancer.

A nanodrug provokes antitumor immune responses via synchronous multicellular regulation for enhanced cancer immunotherapy.

Hepatocellular carcinoma (HCC) exhibits a low response to immunotherapy due to the dense extracellular matrix (ECM) filled with immunosuppressive cells including dendritic cells (DCs) of blocked maturation. Herein, we develop a nanoprodrug self-assembled from polyethylene glycol-poly-4-borono-l-phenylalanine (mPEG-PBPA) conjugating with quercetin (QUE) via boronic ester bonds. In addition, an immune adjuvant of imiquimod (R837) is incorporated. The nanodrug (denoted as Q&R@NPs) is prepared from a simple mixing means with a high loading content of QUE reaching more than 30%. Owing to the acid and reactive oxygen species (ROS) sensitivities of boronic ester bonds, Q&R@NPs can respond to the tumor microenvironment (TME) and release QUE and R837 to synchronously exert multicellular regulation functions. Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression.

Mild near-infrared laser-triggered photo-immunotherapy potentiates immune checkpoint blockade via an all-in-one theranostic nanoplatform.

One of the primary challenges for immune checkpoint blockade (ICB)-based therapy is the limited infiltration of T lymphocytes (T cells) into tumors, often referred to as immunologically "cold" tumors. A promising strategy to enhance the anti-tumor efficacy of ICB is to increase antigen exposure, thereby enhancing T cell activation and converting "cold" tumors into "hot" ones. Herein, we present an innovative all-in-one therapeutic nanoplatform to realize local mild photothermal- and photodynamic-triggered antigen exposure, thereby improving the anti-tumor efficacy of ICB. This nanoplatform involves conjugating programmed death-ligand 1 antibody (aPD-L1) with gadolinium-doped near-infrared (NIR)-emitting carbon dots (aPD-L1@GdCDs), which displays negligible cytotoxicity in the absence of light. But under controlled NIR laser irradiation, the GdCDs produce combined photothermal and photodynamic effects. This not only results in tumor ablation but also induces immunogenic cell death (ICD), facilitating enhanced infiltration of CD8+ T cells in the tumor area. Importantly, the combination of aPD-L1 with photothermal and photodynamic therapies via aPD-L1@GdCDs significantly boosts CD8+ T cell infiltration, reduces tumor size, and improves anti-metastasis effects compared to either GdCDs-based phototherapy or aPD-L1 alone. In addition, the whole treatment process can be monitored by multi-modal fluorescence/photoacoustic/magnetic resonance imaging (FLI/PAI/MRI). Our study highlights a promising nanoplatform for cancer diagnosis and therapy, as well as paves the way to promote the efficacy of ICB therapy through mild photothermal- and photodynamic-triggered immunotherapy.

[Current standard treatments and future outlook for follicular lymphoma].

Follicular lymphoma (FL) is the most common subtype of indolent lymphoma. Survival outcomes for FL have improved since the introduction of anti-CD20 monoclonal antibodies, such as rituximab, and median overall survival has reached 15-20 years. However, FL is an incurable disease that subsequently progresses or relapses, and progression-free and overall survival tend to shorten with repeated relapses. For patients with limited-stage disease, radiation therapy is generally the treatment of choice and results in a median survival of approximately nearly 20 years. For advanced-stage patients with low tumor burden, watchful waiting continues to be the appropriate strategy at present. It remains unclear whether rituximab monotherapy might change this watchful waiting approach and result in a benefit from early intervention in patients with low tumor burden. For advanced-stage patients with high tumor burden, chemoimmunotherapy including rituximab or obinutuzumab followed by maintenance therapy is the standard treatment. For relapsed or refractory patients, treatment options such as chemoimmunotherapy, lenalidomide-rituximab, tazemetostat, chimeric antigen receptor T-cell therapies, and CD3/CD20 bispecific antibodies are available or in development. This review presents current standard treatments, recent advances, and future perspectives on the management of FL.

[Immune microenvironment and immunotherapy resistance in multiple myeloma].

Multiple myeloma (MM) is currently treated with combined immunotherapies targeting the immune microenvironment surrounding MM cells. Although novel immunotherapeutic agents for MM have improved complete response rates and survival time, some patients experience repeated relapses and die of MM because its progression is strongly influenced by the immune microenvironment as well as cytogenetic abnormalities of MM cells. Various studies have elucidated the mechanisms underlying the immunosuppressive immune microenvironment of MM. Recently, single-cell RNA sequencing and cytometry by time-of-flight analysis have revealed spatiotemporal crosstalk between MM and immune cells in the bone marrow of patients with MM. These studies showed that immunosuppression appears in the early stages of MM and becomes stronger as the disease progresses, leading to immunotherapy resistance. Understanding the state of the immune microenvironment in patients with MM is important for developing immunotherapeutic strategies for long-term complete response and cure.

[Recent advances in the treatment of DLBCL].

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all malignant lymphomas, making it the most common subtype. Molecular genetic studies have elucidated the pathogenesis of DLBCL and the causes of its poor prognosis. This basic research has led to the development of novel molecularly targeted therapies that target molecules and cellular antigens in relevant signaling pathways or epigenetic enzymes. Treatment with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone has become the standard of care for newly diagnosed CD20-positive DLBCL with an International Prognostic Index score of 2 to 5, based on its reported efficacy for this indication. In addition, the development of immunotherapy such as anti-CD19-chimeric antigen receptor (CAR)-T therapy and bispecific antibodies such as epcoritamab, mosunetuzumab, and glofitamab has led to a paradigm shift in treatment of relapsed/refractory DLBCL. This review summarizes the evolution of treatment development for DLBCL, as well as the results of the current clinical standard of care and new therapies that are expected to become the standard of care.

Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have both been implicated as drivers of resistance to therapy. Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because of rapid acquisition of tumor-intrinsic resistance. However, the unique PDAC TME may also be a driver of resistance. We found that long-term focal adhesion kinase (FAK) inhibitor treatment led to hyperactivation of the RAS/MAPK pathway in PDAC cells in mouse models and tissues from patients with PDAC. Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. In the TME, cancer-associated fibroblasts (CAFs) impaired the down-regulation of MYC by RAF-MEK inhibition in PDAC cells, resulting in resistance. By contrast, FAK inhibition reprogramed CAFs to suppress the production of FGF1, which can drive resistance to RAF-MEK inhibition. The addition of chemotherapy to combined FAK and RAF-MEK inhibition led to tumor regression, a decrease in liver metastasis, and improved survival in KRAS-driven PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.

Bacterial Lysate-Based Bifunctional mRNA Nanoformulation for Efficient Colon Cancer Immunogene Therapy.

mRNA-based nonviral gene therapy has played an important role in cancer therapy, however, the limited delivery efficiency and therapeutic capacity still require further exploration and enhancement. Immunogene therapy provides a strategy for cancer treatment. Bacteria are tiny single-celled living organisms, many of which can be found in and on the human body and are beneficial to humans. Lactobacillus reuteri is a bacterial member of the gut flora, and recent research has shown that it can reduce intestinal inflammation by stimulating an immunomodulatory response. L. reuteri lysate represents an ideal resource for constructing advanced mRNA delivery systems with immune stimulation potential. Here, we prepared a bifunctional mRNA delivery system DMP-Lac (DOTAP-mPEG-PCL-L. reuteri lysate), which successfully codelivered L. reuteri lysate and IL-23A mRNA, exhibited a high mRNA delivery efficiency of 75.56% ± 0.85%, and strongly promoted the maturation and activation of the immune system in vivo. Both the CT26 abdominal metastasis model and the lung metastasis model also exhibited a good therapeutic effect, and the tumor inhibition rate of DMP-Lac/IL-23A group reached 97.92%. Protein chip technology verified that DMP acted as an immune adjuvant, demonstrating that the L. reuteri lysate could regulate the related immune cells, while IL-23 mRNA caused changes in downstream factors, thus producing the corresponding tumor treatment effect. The DMP-Lac/IL-23A complex exhibited strong anticancer immunotherapeutic effects. Our results demonstrated that this bifunctional mRNA formulation served as a tumor-specific nanomedicine, providing an advanced strategy for colon cancer immunogene therapy.

Integrative pan-cancer analysis reveals the prognostic and immunotherapeutic value of ALKBH7 in HNSC.

The AlkB homolog 7 (ALKBH7) is a nonheme iron (II) α-ketoglutarate-dependent dioxygenase superfamily member, which may affect the progression of several types of human cancer. However, the biological effect, especially the immune-related effect, of ALKBH7 in HNSC remains unclear. Herein, several databases were employed at first to assess the different expression of ALKBH7 as well as their relationship to the prognosis, RNA modification, DNA methylation modulation, immune microenvironment and chemotherapeutic responses of various types of cancers. We found that ALKBH7 was expressed differentially in pan-cancer, and correlated with a satisfied prognosis especially in HNSC. The expression of ALKBH7 was also associated with the level of immune cell infiltration, TMB, MSI, HRD, MMR deficiency, and DNA methyltransferases in a wide variety of cancers, which might be potentially related to the responses against chemotherapeutic agents. Next, the role of ALKBH7 in HNSC was further investigated. Western blot and immunohistochemical analysis in HNSC patients from the NMU cohort showed the reduced ALKBH7 expression level in tumor tissues. In vitro experiments of cell migration, invasion, and proliferation showed a potential protective effect of ALKBH7 in HNSC. Collectively, ALKBH7 might play a protective role in the development and progression of multiple cancers by affecting the metabolism and immune cell infiltration, especially HNSC, which could be a potential biomarker to predict prognosis and chemotherapeutic response.

Targeting VPS18 hampers retromer trafficking of PD-L1 and augments immunotherapy.

Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive antitumor clinical outcomes. However, the limited response rates suggest the incomplete understanding of PD-L1 regulation. Here, we demonstrate that vacuole protein sorting 11 and 18 (VPS11/18), two key players in vesicular trafficking, positively regulate PD-L1 and confer resistance to immune checkpoint blockade therapy. VPS11/18 interact with PD-L1 in endosome recycling accompanied by promoting PD-L1 glycosylation and protein stability. VPS18 deficiency enhances antitumor immune response. Pharmacological inhibition by VPS18 inhibitor RDN impaired PD-L1 member trafficking and protein stability. Combination treatment of RDN and anti-cytotoxic T lymphocyte-associated antigen 4 synergistically enhances antitumor efficacy in aggressive and drug-resistant tumors. RDN exerted lung-preferred distribution and good bioavailability, suggesting a favorable drug efficacy. Together, our study links VPS18/11-mediated trans-Golgi network recycling of PD-L1 and points to a promising treatment strategy for the enhancement of antitumor immunity.