The emergence of immuno-oncology (IO) has led to revolutionary changes in the field of cancer treatment. Despite notable advancements in this field, a thorough exploration of its full depth and extent has yet to be performed. This study provides a comprehensive overview of publications pertaining to IO. Publications on IO from 2014 to 2023 were retrieved by searching the Web of Science Core Collection database (WoSCC). VOSviewer software and Citespace software were used for the visualized analysis. A total of 1,874 articles have been published in the IO domain. The number of publications and citations has been increasing annually. This study also examines the primary research directions within the field of IO. In conclusion, this study offers a comprehensive overview of the opportunities and challenges associated with IO, illuminating the current status of research and indicating potential future trajectories in this rapidly progressing field. This study provides a comprehensive survey of the current research status and hot spots within the field of IO. It will assist researchers in comprehending the current research emphasis and development trends in this field and offers guidance for future research directions.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality globally. Increasing evidence suggests that long non-coding RNAs play a critical role in cancer development, with the small nucleolar RNA host gene family being a key participant in multiple types of carcinogenesis, including HCC. Small nucleolar RNA host gene 1 (SNHG1) is a significant member of the SNHG family. SNHG1 expression consistently increases in various HCC-associated processes, such as cell proliferation, apoptosis, angiogenesis, migration, invasion, and treatment resistance. Higher SNHG1 expression levels predict worse prognosis by positively correlating with clinicopathological features, including larger tumour size, poor differentiation, and advanced stages in patients with HCC. Nevertheless, the precise role of SNHG1 in the initiation and progression of HCC remains unclear. Therefore, this review aims to summarise the current investigations on the pathogenesis of SNHG1 in HCC, highlighting its potential as a molecular marker for early prediction and prognostic assessment. As a multifunctional modulator, SNHG1 is extensively involved in molecular signalling pathways in HCC progression and is valuable for therapeutic targeting.

Breast cancer ranks as the most prevalent cancer type impacting women globally, both in terms of incidence and mortality rates, making it a major health concern for females. There's an urgent requirement to delve into new cancer treatment methods to improve patient survival rates.

Immunotherapy has gained recognition as a promising area of research in the treatment of breast cancer, with targeted immune checkpoint therapies demonstrating the potential to yield sustained clinical responses and improve overall survival rates. Presently, the predominant immune checkpoints identified on breast cancer cells include CD47, CD24, PD-L1, MHC-I, and STC-1, among others. Nevertheless, the specific roles of these various immune checkpoints in breast carcinogenesis, metastasis, and immune evasion have yet to be comprehensively elucidated. We conducted a comprehensive review of the existing literature pertaining to breast cancer and immune checkpoint inhibitors, providing a summary of findings and an outlook on future research directions.

This article reviews the advancements in research concerning each immune checkpoint in breast cancer and their contributions to immune evasion, while also synthesizing immunotherapy strategies informed by these mechanisms. Furthermore, it anticipates future research priorities, thereby providing a theoretical foundation to guide immunotherapy as a potential interventional approach for breast cancer treatment.

Knowledge of immune checkpoints will drive the creation of novel cancer therapies, and future breast cancer research will increasingly emphasize personalized treatments tailored to patients' specific tumor characteristics.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, abnormal tumor vasculature and excess lactate contribute to tumor immunosuppression and confer resistance to ICB therapy, seriously limiting its clinical application. Here, we have developed a bioresponsive nanoreactor, ALMn, which consists of hollow manganese dioxide nanoparticles with encapsulation of lactate oxidase and L-Arginine, to overcome immunosuppression and sensitize ICB therapy. In the tumor microenvironment, lactate oxidase catalyzes lactate to produce hydrogen peroxide, which subsequently oxidizes L-Arginine to generate nitric oxide for vascular normalization. Through cascade reactions, ALMn effectively depletes excess lactate and normalize tumor vasculature, reshaping the immunosuppressive phenotype to an immune-activated one. Transcriptomics and immunological analyses prove that ALMn facilitates the infiltration and activation of effector cells, further potentiating antitumor immunity. Consequently, ALMn sensitizes anti-PD-L1 therapy, significantly suppressing tumor growth with an 83.7 % suppression, and prolonging the survival of mice, with the median survival time increasing from 29.5 days to 54.5 days. Our study demonstrates that ALMn effectively alleviates tumor immunosuppression and synergizes with anti-PD-L1, which shows promise in boosting ICB therapy.

Immunotherapy represents a highly promising modality in cancer treatment, with substantial advancements in therapeutic strategies. The primary challenge lies in enhancing the efficacy of immunotherapy approaches. Here, novel cryo-inactivated cancer cells (CICC) derived magnetic micromotors (CICC@FeMnP) are reported for tumor synergistic immunotherapy. Through the magnetic control, the CICC@FeMnP micromotors can on-demand target and accumulate at the tumor site. The FeMnP can induce ferroptosis and then trigger immunogenic cell death of tumor cells. The CICC containing the whole cancer antigen can conduct vaccination effects. Together with the Mn2+-mediated cGAS-STING pathway to stimulate the immune response, substantial anti-tumor immune effects can be achieved. Importantly, the CICC@FeMnP micromotors not only facilitate the establishment of a collaborative anti-tumor immune network to enhance effective tumoricidal immunity but also induce long-lasting immune memory effects. These results contribute to the inhibition of tumor progression, recurrence and lung metastasis, thereby prolonging the overall survival of tumor-bearing mice. This work underscores the potential of an engineered biohybrid micromotor system as an alternative therapeutic approach in immunotherapy to enhance efficacy against tumors.

Despite the notable success of cancer immunotherapy, its effectiveness is often limited in a significant proportion of patients, highlighting the need to explore alternative tumor immune evasion mechanisms. Adenosine, a key metabolite accumulating in hypoxic tumor regions, has emerged as a promising target in oncology. Inhibiting the adenosinergic pathway not only inhibits tumor progression but also holds potential to enhance immunotherapy outcomes. Multiple therapeutic strategies targeting this pathway are being explored, ranging from preclinical studies to clinical trials. This review examines the complex interactions between adenosine, its receptors, and the tumor microenvironment, proposing strategies to target the adenosinergic axis to boost anti-tumor immunity. It also evaluates early clinical data on pharmacological inhibitors of the adenosinergic pathway and discusses future directions for improving clinical responses.

V-domain Ig suppressor of T cell activation (VISTA) is a recently characterized as immune checkpoint regulator with critical roles in modulating immune responses across pathological contexts. In cancer, VISTA contributes to immune evasion by sustaining an immunosuppressive tumor microenvironment, emerging as a promising target for immunotherapeutic intervention. In contrast, in autoimmune diseases, VISTA preserves peripheral immune tolerance and suppresses aberrant immune activation, thereby preventing tissue destruction. This functional dichotomy reflects the complexity of VISTA-mediated signaling, which is modulated by cellular context, microenvironmental cues, and disease stage. Recent studies have elucidated key aspects of VISTA biology, including its structural features, ligand interactions, and context-dependent expression patterns. VISTA operates as a co-inhibitory molecule in cancer, while exerting co-stimulatory or regulatory effects in autoimmunity. This review provides a comprehensive overview of VISTA's discovery, molecular mechanisms, and dual roles in cancer and autoimmune pathogenesis. Furthermore, the current status of VISTA-targeted therapeutic strategies is critically examined, highlighting the translational challenges posed by discrepancies between preclinical models and clinical trial outcomes. Finally, the potential of targeting VISTA within the broader paradigm of immune checkpoint plasticity is discussed, with emphasis on overcoming compensatory immune resistance to enhance therapeutic efficacy. A deeper mechanistic understanding of VISTA is essential for the rational design of future immunomodulatory therapies tailored to specific disease contexts.

Nanodrug delivery systems (NDDS) have demonstrated broad application prospects in disease treatment, prevention, and diagnosis due to several advantages, including functionalization capability, high drug-loading capacity, drug stability protection, and the enhanced permeability and retention (EPR) effect. However, their clinical translation still faces multiple challenges, including rapid clearance by the reticuloendothelial system (RES), poor targeting specificity, and insufficient efficiency in crossing biological barriers. To address these limitations, researchers have developed the biological carrier-mediated nanomedicine hitchhiking strategy (BCM-NHS), which leverages circulating cells, proteins, or bacteria as natural "mobile carriers" to enhance drug delivery. This approach enables nanocarriers to inherit the intrinsic biological properties, endowing them with immune evasion, prolonged circulation, dynamic targeting, biocompatibility, biodegradability, and naturally optimized biological interfaces. Here, a systematic overview of the BCM-NHS is provided. First, the review delves into the methods of nanoparticles (NPs) binding and immobilization, encompassing both the surface-attachment-mediated "backpack" strategy and the encapsulation-based "Trojan horse" strategy. Second, the classification of biological carriers, including both cell-based and non-cell-based carriers, is elucidated. Third, the physical properties and release mechanisms of these nanomaterials are thoroughly described. Finally, the latest applications of BCM-NHS in therapeutic and diagnostic contexts across various disease models including tumor, ischemic stroke, and pneumonia are highlighted.

Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions.

Tumor-Infiltrating Lymphocytes (TILs) immunotherapy is a highly promising treatment for Non-small Cell Lung Cancer (NSCLC), which is responsible for 18% of all cancer-related deaths. The heterogeneity of TILs remains poorly understood. Here, we utilized combined single-cell RNA (scRNA)/T cell receptor sequencing (scTCR-seq) data from lung adenocarcinoma (LUAD) patients. Naïve CD4+ and effector memory CD8+ T cells were increased in tumor tissue compared with circulating blood samples. Activated signaling pathways were detected, and GZMA was identified as a potential novel diagnostic biomarker. During the transitional phase, macrophages (FTL) and dendritic (AIF1) cells transported the most CD3 TCR clones to T cells, while cytotoxicity CD8+ T (NKG7) cells transported to terminal exhausted CD8+ T cells. In both transition and expansion phases, T helper cells (CXCL13) are transported to regulatory T cells (Tregs). Additionally, we investigated the expression profiles of key cytokines, checkpoint receptors, and their ligands. Cytotoxicity CD8+ T cells (CCL5 and IFNG), T helper cells (FTL, TNFRSF4, and TIGIT), and regulatory T cells (CTLA4, TIGIT and FTL) exhibited functional roles in both primary and metastatic tumor stages. Taken together, our study provides a single-cell resolution of the TIL immune landscape and suggests potential treatment strategies to overcome drug resistance.

Cancer vaccines show promise by eliciting tumor-specific cytotoxic T lymphocytes (CTL) responses. Efficient cytosolic co-delivery of antigens and adjuvants to dendritic cells (DCs) is crucial for vaccines to induce anti-tumor immunity. However, peptide- or nucleic acid-based biomolecules like tumor antigens and STING agonist cyclic-di-GMP (cdGMP) are prone to endosomal degradation, resulting in low cytosolic delivery and CTL response rates. Cationic nanocarriers can improve cytosolic delivery, but their positive charges induce off-target effects. Here, we develop cationic poly(ester amide) based nanoparticles co-loaded with antigens and adjuvant cdGMP (NP(cG, OVA)) for efficient cytosolic delivery and swallow them within antigen self-presenting DCs-derived dendrosomes (ODs) for lymph nodes (LNs) homing. The constructed dendrosomes swallowing nanovaccines ODs/NP(cG, OVA) demonstrated significantly reduced liver accumulation and enhanced LNs and DCs targeting compared to NP(cG, OVA). ODs/NP(cG, OVA) effectively cross-dressed the antigen epitopes on the shell to DCs and facilitated internalization of NP(cG, OVA), realizing DCs cytosolic co-delivery of antigens and adjuvants, thereby promoting antigen presentation, maturation and inflammatory cytokines secretion of DCs. Consequently, DCs stimulated by ODs/NP(cG, OVA) effectively induced activation, proliferation, and differentiation of antigen-specific CTLs that provided robust immune protection against tumor invasion. This work presents a powerful vaccine strategy for cancer immunotherapy.

Peptide-drug conjugates (PDCs) have emerged as a next-generation therapeutic platform, combining the target specificity of peptides with the pharmacological potency of small-molecule drugs. As an evolution beyond antibody-drug conjugates (ADCs), PDCs offer distinct advantages, including enhanced cellular permeability, improved drug selectivity, and versatile design flexibility. This review provides a comprehensive analysis of the fundamental components of PDCs, including homing peptide selection, linker engineering, and payload optimization, alongside strategies to address their inherent challenges, such as stability, bioactivity, and clinical translation barriers. Therapeutic applications of PDCs span oncology, infectious diseases, metabolic disorders, and emerging areas like COVID-19, with several conjugates advancing in clinical trials and achieving regulatory milestones. Innovations, including bicyclic peptides, supramolecular architectures, and novel linker technologies, are explored as promising avenues to enhance PDC design. Additionally, this review examines the clinical trajectory of PDCs, emphasizing their therapeutic potential and highlighting ongoing trials that exemplify their efficacy. By addressing limitations and leveraging emerging advancements, PDCs hold immense promise as targeted therapeutics capable of addressing complex disease states and driving progress in precision medicine.

Interferon-gamma (IFN-γ), a cytokine essential for activating cellular immune responses, plays a crucial role in cancer immunosurveillance and the clinical success of immune checkpoint blockade therapy. In this study, we show that Argonaute 2 (AGO2), a key mediator in small RNA-guided gene regulation, inversely correlates with tumor responsiveness to IFN-γ and the efficacy of immunotherapy. Mechanistically, IFN-γ upregulates miR-1246 expression in tumor cells, enhancing its interaction with AGO2. This miR-1246-AGO2 complex disrupts IFN-γ-mediated signal transducer and activator of transcription 1 (STAT1) phosphorylation by stabilizing protein tyrosine phosphatase non-receptor 6 (PTPN6) mRNA, thereby suppressing the expression of downstream C-X-C motif chemokine ligands (CXCLs), IFN-stimulated genes (ISGs), and human leukocyte antigen (HLA) molecules, which collectively contribute to tumor immune evasion. In preclinical cancer models, inhibiting AGO2 with BCI-137 or targeting miR-1246 with its antagomir re-sensitizes tumor cells to IFN-γ, leading to the enhanced recruitment, activation, and cytotoxicity of CD8+ T cells and ultimately improving immunotherapy efficacy.

Hepatocellular carcinoma (HCC) is the dominant type of liver cancer and is associated with a high mortality rate. However, HCC lacks biomarkers for diagnosis and immune therapy response. Tumor-derived exosomes (TDEs) carcinogen-specific molecules have been used for screening multiple biomarkers. This study aimed to identify new biomarkers for the diagnosis of HCC and response to immune checkpoint blockade (ICB) therapy.

Analysis of differentially expressed genes (DEGs) in HCC and normal tissues was integrated using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ExoCarta datasets. The expression of CCT3 was validated in samples from patients with HCC using quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC) techniques.

Exosomal CCT3 was identified as a potential biomarker with significant impact. The expression of CCT3 in different tumor stages and normal tissues adjacent to the tumors (NATs) was validated using qPCR, western blotting, and IHC. CCT3 expression significantly increased the number of activated natural killer cells in HCC, as confirmed by qPCR and IHC. CCT3 expression significantly increases the expression of immune checkpoints in HCC. HCC-derived exosomes significantly increase the enrichment of CCT3.

Exosomal CCT3 is a biomarker for diagnosis and ICB therapy of HCC via MYC pathway activation and immune infiltration.

Cancer immunotherapy such as immune checkpoint blockade (ICB) therapy has made important breakthroughs in cancer treatment, however, currently only parts of cancer patients benefit from ICB therapy. The suppressive tumor immune microenvironment (TIME) impedes the treatment response of immunotherapy, indicating the necessity to explore new treatment targets. Here, we reported a new potential immunotherapeutic target, Dickkopf-3 (DKK3), for cancer treatment. DKK3 expression is up-regulated in the tumors from multiple cancer types, and high DKK3 expression is associated with worse survival outcome across different cancers. We observed that DKK3 directly inhibits the activation of CD8+ T cells and the Th1 differentiation of CD4+ T cells ex vivo. Also, by establishing four different mouse cancer models, we found that DKK3 blockade triggers effective anti-tumor effects and improve the survival of tumor-bearing mice in vivo. DKK3 blockade also remodels the suppressive TIME of different cancer types, including the increased infiltration of CD8+ T cells, IFN-γ+CD8+ T cells, Th1 cells, and decreased infiltration of M2 macrophages and MDSCs in the TIME. Moreover, we found that combined blockade of DKK3 and PD-1 induces synergistic tumor-control effect in our mouse cancer model. Therefore, our study reveals the impact of DKK3 in the TIME and cancer progression, which suggests that DKK3 is a novel and promising immunotherapeutic target for enhanced cancer immunotherapy.

The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded with succinate (SMPs) can remodel the metabolic state of TAMs. SMPs promote classical M1-like polarization of macrophages by enhancing glycolysis and attenuating the tricarboxylic acid (TCA) cycle in a protein succinylation-dependent manner. Mechanistically, succinate is delivered into the mitochondria and nucleus by SMPs, leading to succinylation of isocitrate dehydrogenase 2 (IDH2) and histone H3K122 within the lactate dehydrogenase A (Ldha) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane-derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification-based tumor immunotherapy.

Unleashing T cell function is critical for efficacious cancer immunotherapy. Here, we present an in vivo T cell activation strategy by silencing Casitas B-lineage lymphoma proto-oncogene b (Cbl-b), an intracellular checkpoint, to effectively combat solid tumors. The polymersomes are able to efficiently load and deliver siRNA against cblb to T cells both in vitro and in vivo, successfully silencing the cblb gene expression in primary T cells and enhancing the IL-2 receptor CD25 expression, which in turn enhances T cell function and prevents T cell exhaustion. In vitro and in vivo studies showed that siRNA against cblb caused an effective inhibition of tumor progression in subcutaneous B16-F10 and LLC models, in which a significant increase of effector T cells in peripheral blood mononuclear cells and an increase of effector T cells and a significant decrease of Treg cells in the tumor were clearly observed. This polymersome-mediated down-regulation of the cblb gene in T cells provides a promising approach for activating T cells and enhancing their anti-tumor capacity.

Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.

Immunotherapy, particularly immune checkpoint blockade (ICB), has opened the era of modern oncology, offering significant promise for modern oncology. However, the efficacy of immunotherapy is frequently curtailed by the immunosuppressive tumor microenvironment (ITM), a milieu shaped by tumor metabolic reprogramming. Herein, a novel tumor microenvironment-responsive nanocapsules (DNMCs) were developed that simultaneously modulate tumor metabolism and the ITM to enhance the effectiveness of chemo-immunotherapy. DNMCs consist of an acidic and redox-sensitive metal-organic framework (MOF) encapsulating Doxorubicin (DOX) and the indoleamine-2,3-dioxygenase1 (IDO1) inhibitor NLG919. In the tumor microenvironment, DNMCs degrade, rapidly releasing DOX and NLG919. DOX induces immunogenic cell death (ICD), while NLG919 regulates amino acid metabolism by modulating IDO1 activity, thereby reversing the immunosuppressive of ITM. Consequently, DNMCs elicit effective anti-tumor immune responses, characterized by an increased density of tumor-infiltrating CD8+ cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells (Tregs), thus effectively suppressing pancreatic cancer growth in KPC mice through combined chemo-immunotherapy. Overall, DNMCs exhibit significant tumor growth inhibition in pancreatic cancer patient-derived organoids (PDOs) and mouse models. This study presents a promising approach to enhancing chemo-immunotherapy by targeting tumor metabolic reprogramming and augmenting immune response against malignant tumors.

The ability to recognize antigen epitope is crucial for generating an effective immune response. By engineering these epitopes, researchers can reduce on-target/off-tumor toxicity associated with targeted immunotherapy. Recent studies indicate that employing various gene editing tools to modify the epitopes of healthy hematopoietic stem and progenitor cells (HSPCs) can protect these cells from toxicity during tumor eradication, all while preserving their differentiation and function. This advancement greatly enhances the safety and efficacy of tumor immunotherapy.

Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment. In recent years, immune therapeutics targeting T lymphocytes, such as immune checkpoint blockade (ICB) and CAR-T, have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers. However, responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients. As major components of most solid tumors, myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity, thus determining tumor progression as well as therapeutic responses. In this review, we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells. We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells, and discuss recent progress in revealing different mechanisms-chemotaxis, proliferation, survival, and alternative sources-involved in the infiltration and accumulation of myeloid cells within tumors. Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.

Despite the transformative impact of programmed cell death protein-1 (PD-1) blockade therapy on metastatic/advanced solid tumor treatment, its efficacy is hindered by a limited response rate. Platelets play a pivotal role in tumor metastasis by shielding circulating tumor cells and secreting immunosuppressive factors. We here demonstrate that selectively inducing apoptosis in tumor-associated platelets (TAPs) using ABT-737-loaded nanoparticles (cyclic arginine-glycine-aspartate containing peptide-modified ABT-737-loaded nanoparticles [cRGD-NP@A]) enhances the anti-metastatic efficacy of the anti-PD-1 antibody (aPD-1). cRGD-NP@A specifically binds to TAPs, disrupting platelet-tumor cell interactions and exposing tumor cells to immune surveillance in vivo. Combined with aPD-1, cRGD-NP@A substantially augments immune activation and reduces TAP-derived immunosuppressive factors, notably transforming growth factor β1 (TGF-β1), consequently improving anti-metastatic outcomes across multiple metastasis-bearing animal models without observable adverse effects. Our study underscores the importance of depleting TAPs to enhance PD-1 blockade therapy, presenting a promising strategy to improve response rates and clinical outcomes for patients with metastatic cancer.

Irreversible electroporation (IRE) is a novel local tumor ablation approach with the potential to activate the host's immune system. However, this approach is insufficient to prevent cancer progression, and complementary approaches are required for effective immunotherapy.

To assess the immunomodulatory effects and mechanism of IRE combined anti-programmed cell death protein 1 (PD-1) treatment in subcutaneous pancreatic cancer models.

C57BL-6 tumor-bearing mice were randomly divided into four groups: Control group; IRE group; anti-PD-1 group; and IRE + anti-PD-1 group. Tumor-infiltrating T, B, and natural killer cell levels and plasma concentrations of T helper type 1 cytokines (interleukin-2, interferon-γ, and tumor necrosis factor-α) were evaluated. Real-time PCR was used to determine the expression of CD8 (marker of CD8+ T cells) in tumor tissues of the mice of all groups at different points of time. The growth curves of tumors were drawn.

The results demonstrated that the IRE + anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration, including CD4+ and CD8+ T cells compared with the control group. Additionally, the IRE + anti-PD-1 group showed increased infiltration of natural killer and B cells, elevated cytokine levels, and higher CD8 mRNA expression. Tumor volume was significantly reduced in the IRE + anti-PD-1 group, indicating a more pronounced therapeutic effect.

The combination of IRE and anti-PD-1 therapy promotes CD8+ T cell immunity responses, leading to a more effective reduction in tumor volume and improved therapeutic outcomes, which provides a new direction for ablation and immunotherapy of pancreatic cancer.

Radiotherapy (RT) effectiveness is limited by low DNA damage in tumor cells, surrounding tissue harm, and tumor radioresistance with active DNA repair. Herein, we have engineered a two-dimensional nanomaterial consisting of MXene nanosheets at its core, coated with gold nanorods and a cisplatin shell, and further modified with polyvinyl alcohol, referred to as APMP. The APMP exploits its distinctive electronic properties and photothermal effects to augment radiosensitivity and impede DNA damage repair mechanisms. In vitro experiments demonstrate that APMP elevates reactive oxygen species (ROS) production to approximately 2.6 times higher than that achieved with radiotherapy alone, thereby significantly enhancing the sensitivity to radiotherapy. Combining APMP with photothermal therapy (PTT) and RT is a promising glioblastoma treatment strategy, achieving tumor destruction via localized hyperthermia and overcoming radioresistance. This approach achieves precise tumor targeting, reducing side effects and enhancing therapeutic response in preclinical models. The novel core-shell design enables potent radiotherapy-specific radiosensitizers that drive immunogenic cell death, enhancing glioblastoma combination immunotherapy. This universal strategy heralds a new era in integrating radiotherapy sensitizers with immunotherapy.

The immunosuppressive network formed by the enhanced crosstalk between tumor cells and various types of immune cells may ultimately lead to the formation of tumor immunosuppressive microenvironment (TIME). The Golgi apparatus (GA) of tumor cells is a key organelle in the formation of a tumor immunosuppressive network. However, there are no studies to show whether interfering with the GA of tumor cells can reshape the immunosuppressive network to enhance the effectiveness of immunotherapy. Therefore, the tumor cell GA-targeting self-assembled peptide (NF-1) is tailored, and confirmed that NF-1 treatment can achieve an effective immunotherapy and found that tumor cell-derived GA-dependent migration inhibitory factor (MIF) mediates the formation of immunosuppressive network in breast cancer (BRCA) through multi-omics analysis, in vivo, and in vitro experiments. NF-1 treatment-induced MIF reduction can reshape the immunosuppressive network and convert a "cold" tumor into a "hot" tumor, thus enabling immunotherapy in BRCA and enhancing the ICB efficacy in colon adenocarcinoma (COAD). This study presents a general strategy for interfering with tumor GA for effective immunotherapy in BRCA, COAD, and other cancers characterized by a "cold" immune microenvironment.

The deficiency in immunogenicity and the presence of immunosuppression within the tumor microenvironment significantly hindered the efficacy of immunotherapy. Consequently, a nanoformulation containing metal sulfide of FeS and GSDMD plasmid (NPFeS/GD) had been developed to effectively augment antitumor immune responses through dual activation of immunogenic PANoptosis and ferroptosis, as well as reprogramming immunosuppressive effects via H2S amplification. The bioactive NPFeS/GD exhibited controlled release of GSDMD plasmid, H2S, and Fe2+ in response to the tumor microenvironment. Fe2+, H2S, and the expression of GSDMD protein could effectively elicit highly immunogenic PANoptosis and ferroptosis. Furthermore, releasing H2S could mitigate the overexpression of indoleamine 2,3-dioxygenase1 (IDO1) induced by immunogenic PANoptotic and ferroptotic cell death and disrupt the activity of IDO1. Consequently, NPFeS/GD effectively triggered the antitumor innate and adaptive immune responses through induction of PANoptotic and ferroptotic cell death and reshaped the tumor immunosuppressive microenvironment to enhance antitumor immunotherapy for metastasis inhibition. This study unveiled the significant potential of immunogenic PANoptosis and ferroptosis in H2S gas therapy for enhancing tumor immunotherapy, offering novel insights and ideas for the rational design of nanomedicine to enhance tumor immunogenicity while reprogramming the tumor immunosuppressive microenvironment.

Colorectal cancer (CRC) usually creates an immunosuppressive microenvironment, thereby hindering immunotherapy response. Effective treatment options remain elusive. Using scRNA-seq analysis in a tumor-bearing murine model, it is found that lobeline, an alkaloid from the herbal medicine lobelia, promotes polarization of tumor-associated macrophages (TAMs) toward M1-like TAMs while inhibiting their polarization toward M2-like TAMs. Additionally, lobeline upregulates mRNA expression of secreted Ly-6/UPAR-related protein 1 (Slurp1) in cancer cells. The inhibitory effects of lobeline on tumor load and TAM polarization are almost completely eliminated when Slurp1-deficient MC38 cells are subcutaneously injected into mice, suggesting that lobeline exerts an antitumor effect in a Slurp1-dependent manner. Furthermore, using target-responsive accessibility profiling, MAPK14 is identified as the direct target protein of lobeline. Mechanistically, upon binding to MAPK14 in colon cancer cells, lobeline prevents nuclear translocation of MAPK14, resulting in decreased levels of phosphorylated p53. Consequently, negative transcriptional regulation of SLURP1 by p53 is suppressed, leading to enhanced transcription and secretion of SLURP1. Finally, combination therapy using lobeline and anti-PD1 exhibits stronger antitumor effects. Taken together, these findings suggest that remodeling the immunosuppressive microenvironment using small-molecule lobeline may represent a promising therapeutic strategy for CRC.

Immune checkpoint blockade (ICB) therapies, particularly anti-PD-1, benefit only a limited subset of colorectal cancer (CRC) patients. G-protein signaling modulator 1 (GPSM1) is implicated in immunity and oncology, yet its role in regulating the CRC tumor microenvironment (TME) and contributing to anti-PD-1 resistance remains poorly understood.

We employed single-cell RNA sequencing and multiplex immunofluorescence on tumor samples from anti-PD-1-resistant CRC patients to evaluate GPSM1 expression and its impact on macrophage polarization. An orthotopic CRC xenograft model in C57BL/6 mice was used to assess the role of GPSM1 in vivo. An in vitro co-culture system, alongside mass cytometry and flow cytometry, explored GPSM1's biological functions within the TME. We further used ChIP-PCR, mass spectrometry, and co-immunoprecipitation to elucidate the mechanisms regulating GPSM1 activity.

GPSM1 expression was significantly elevated in anti-PD-1-resistant CRC tissues. Enhanced GPSM1 levels promoted anti-PD-1 resistance by driving macrophage polarization toward an immunosuppressive M2 phenotype, facilitating their infiltration into the TME. We identified the deubiquitinase USP9X as a key factor preventing GPSM1 degradation through K63-polyubiquitination. This stabilization of GPSM1 led to MEIS3 nuclear translocation, activating macrophage colony-stimulating factor expression. Importantly, ruxolitinib emerged as a promising GPSM1-targeting candidate, demonstrating improved efficacy in combination with anti-PD-1 therapy in both microsatellite instability-high and microsatellite stable CRC models.

Our findings highlight the pivotal role of GPSM1-driven M2 macrophage infiltration in mediating anti-PD-1 resistance in CRC. Targeting GPSM1 offers a novel therapeutic strategy to enhance ICB efficacy, potentially broadening the patient population that may benefit from these therapies.

Clinically, multimodal therapies are adopted worldwide for the management of cancer, which continues to be a leading cause of death. In recent years, immunotherapy has firmly established itself as a new paradigm in cancer care that activates the body's immune defense to cope with cancer. Immunotherapy has resulted in significant breakthroughs in the treatment of stubborn tumors, dramatically improving the clinical outcome of cancer patients. Multiple forms of cancer immunotherapy, including immune checkpoint inhibitors (ICIs), adoptive cell therapy and cancer vaccines, have become widely available. However, the effectiveness of these immunotherapies is not much satisfying. Many cancer patients do not respond to immunotherapy, and disease recurrence appears to be unavoidable because of the rapidly evolving resistance. Moreover, immunotherapies can give rise to severe off-target immune-related adverse events. Strategies to remove these hindrances mainly focus on the development of combinatorial therapies or the exploitation of novel immunotherapeutic mediations. Nanomaterials carrying anticancer agents to the target site are considered as practical approaches for cancer treatment. Nanomedicine combined with immunotherapies offers the possibility to potentiate systemic antitumor immunity and to facilitate selective cytotoxicity against cancer cells in an effective and safe manner. A myriad of nano-enabled cancer immunotherapies are currently under clinical investigation. Owing to gaps between preclinical and clinical studies, nano-immunotherapy faces multiple challenges, including the biosafety of nanomaterials and clinical trial design. In this review, we provide an overview of cancer immunotherapy and summarize the evidence indicating how nanomedicine-based approaches increase the efficacy of immunotherapies. We also discuss the key challenges that have emerged in the era of nanotechnology-based cancer immunotherapy. Taken together, combination nano-immunotherapy is drawing increasing attention, and it is anticipated that the combined treatment will achieve the desired success in clinical cancer therapy.

Adding pembrolizumab, an anti-PD-1 antibody approved for treatment of head and neck squamous cell carcinoma (HNSCC) to neoadjuvant (induction-) chemotherapy utilizing docetaxel and cisplatin (TP) followed by radiotherapy may improve outcome in larynx organ-preservation (LOP) that is investigated in the European Larynx-Organ preservation Study (ELOS). As biomarkers for response to TP and pembrolizumab +TP are missing but may include cytokines, this work aims on determining cytokines potentially linked to outcome as prognostic markers sufficient to predict and/or monitor response to successful LOP.

Collagenase IV digests were generated from 47 histopathological confirmed HNSCC tumor samples and seeded in 96-well plates containing pembrolizumab, docetaxel, cisplatin either solely or in binary or ternary combination. According to the FLAVINO protocol, supernatants were collected after 3 days, adherent cells fixed using ethanol, air-dried and pan-cytokeratin positive epithelial cells counted using fluorescence microscopy. The cytokines IL-6, IL-8, IFN-γ, IP-10, MCP-1, TNF-α, and VEGF in the supernatant were quantified by sandwich ELISA.

The mode of interaction between pembrolizumab and TP was assessed and correlated to outcome (overall, disease-specific and progression-free survival of patients). Suppression of MCP-1, IFN-γ and IL-6 production by pembrolizumab + TP exceeding the suppressive effect of TP was detected in the majority of samples and linked to improved survival. Multivariate Cox proportional hazard regression modeling revealed MCP-1, IFN-γ and IL-6 as independent outcome predictors.

Comparing response to TP vs. pembrolizumab vs. TP + pembrolizumab may allow for identification of patients with superior outcome independent from treatment applied.

Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co-delivery of both agents is still highly desirable. In this study, a strategy for co-delivering small interfering RNA (siRNA) encapsulated in vesicle-like nanoparticles (VNPsiRNA) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNPsiRNA. The resulting VNPsiRNACpMTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNPsiRNACpMTO through chemo-immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co-delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment.

Cancer treatment has witnessed revolutionary advancements marked by the emergence of immunotherapy, specifically immune checkpoint blockade (ICB). However, the inherent low immunogenicity of tumor cells and the intricate immunosuppressive network within the tumor microenvironment (TME) pose significant challenges to the further development of immunotherapy. Nanotechnology has ushered in unprecedented opportunities and vast prospects for tumor immunotherapy. Nevertheless, traditional nano-formulations often rely on inducing apoptosis to kill cancer cells, which encounters the issue of immune silencing, hindering effective tumor immune activation. The non-apoptotic modes of regulated cell death (RCD), including pyroptosis, ferroptosis, autophagy, necroptosis, and cuproptosis, have gradually garnered attention. These non-apoptotic cell death pathways can induce effective immunogenic cell death (ICD), enhancing cancer immunotherapy. This review comprehensively explores advanced nano-formulation design strategies and their applications in enhancing cancer immunotherapy by promoting non-apoptotic RCD in recent years. It also discusses the potential advantages of these strategies in inducing tumor-specific non-apoptotic RCD. By deeply understanding the significance of non-apoptotic RCD in synergistic cancer immunotherapy, this article provides valuable insights for developing more advanced nano-delivery systems that can robustly induce highly immunogenic non-apoptotic modes, offering novel research and development avenues to address the clinical challenges encountered by immunotherapy represented by ICB.

Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review focuses on the crucial role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint blockade. Studies suggest that the composition of the gut microbiome may influence the response to immunotherapy, with specific bacterial strains able to promote an anti-tumor immune response. On the other hand, dysbiosis may increase the risk of adverse effects, such as immune-mediated colitis. Interventions aimed at modulating the microbiome, including the use of probiotics, prebiotics, fecal microbial transplantation, or dietary modifications, represent promising strategies to increase treatment efficacy and reduce toxicity. The combination of immunotherapy with the microbiome-based strategy opens up new possibilities for personalized treatment. In addition, factors such as physical activity and nutritional supplementation may indirectly influence the gut ecosystem and consequently improve treatment outcomes in refractory patients, leading to enhanced patient responses and prolonged survival.

CD5 is a pan T-cell marker expressed by all T-cells and a subset of B-cells, i.e., B1a cells. The significance of CD5 is evident from its functions, starting from T-cell development, antigen priming, activation, and effector response to the maintenance of tolerance. Varying CD5 expression and signaling in response to TCR-pMHC complex avidity is associated with thymic selection, competency, and effector response. Altered CD5 expression is associated with immunological and diseased conditions such as CD5-/low infiltrating T-cells in solid tumors, CD5hi T-cells in anergy conditions, CD5-/low phenotype of leukemic T-cells, high CD5 expression by regulatory T-cells, CD5lowphenotype of autoreactive T-cells, etc. A low CD5 expression triggers activation-induced cell death upon antigenic stimulation. There are three forms of CD5: membrane CD5 (mCD5), intracellular CD5 (cCD5) and soluble CD5 (sCD5). mCD5 and cCD5 are generated from conventional and non-conventional mRNA variants, i.e., E1A and E1B, respectively. E1B variant encoding cCD5 is derived from a human endogenous retrovirus segment inserted 8.2 kb upstream to conventional E1A exon. Various conditions, such as leukemia, exposure to hydrocarbon, hypoxia, etc., can trigger E1B transcription and, thus, cCD5 expression. Blocking mCD5 with mAb can restore immune response, effectively targeting cancer. Understanding cCD5, linked to leukemogenesis, can offer new avenues of immunotherapy.

Multispecific therapeutics hold significant promise in drug delivery, protein degradation, and cell recruitment to address clinical issues of tumor heterogeneity, resistance, and immune evasion. However, their modular engineering remains challenging. We developed a targeted degradation platform, termed multivalent nanobody-targeting chimeras (mNbTACs), by encoding diverse nanobody codons on a circular template using DNA printing technology. The homo- or hetero- mNbTACs specifically recognized membrane targets in a multivalent manner and simultaneously recruited scavenger receptors to favor clathrin-/caveolae-dependent endocytosis and lysosomal degradation of multiple proteins with high efficiency and selectivity. We demonstrated that a bispecific doxorubicin-loaded mNbTAC, named Doxo-mvNbsPPH, passively accumulated at tumor sites, specifically interacted with PD-L1 and HER2 targets, and was rapidly transported into lysosome, inducing potent immunogenic cell death and alleviating immune checkpoint evasion. The synergistic boosting of innate and adaptive immunity promoted the infiltration and proliferation of CD8+ T cells in tumor microenvironment (an 11-fold increase) with high toxicity and low exhaustion, eventually enhancing antitumor efficacy. Our mNbTAC platform provides multispecific therapeutics with variable valences and programmed species, whereas it induces targeted protein degradation through multireceptor-mediated endocytosis and lysosomal degradation without the need for lysosome-targeting receptors, representing a general and modular tool to harness extracellular proteome for disease treatment.

Safely and effectively harnessing innate immunity to boost cancer immunotherapy is promising yet challenging. Hence, we have developed a series of programmable aptamer-based multispecific engagers by encoding various artificial aptamer-drug codons with DNA-templated polymerization, aiming to broadly boost innate and adaptive immunity for antitumor therapy. All circular single-stranded multivalent aptamer-drug conjugates (os-mvApDCs) had a dendritic structure, precise size, and excellent stability, enabling prolonged blood circulation, targeted tumor accumulation, and rapid multireceptor-mediated endocytosis. A trispecific engager (Sl/Pd/Mjos-mvApDCsSMT), targeting PD-1 on CD8+ T cells and PD-L1/c-Met on tumor cells, recruited large amounts of immune cells into the tumor and released cytotoxic MMAE and immunomodulators, inducing severe cell death and broad activation of innate immunity. When combined with the αPD-1 blockade, there was a significant increase in the number of CD8+ T cells (10-fold increase versus untreated control) engaged and expanded in the tumor, exhibiting potent function (IFN-γ+/GzmB+) and low exhaustion (PD-1+TIM-3+). The orchestrated innate and adaptive immunity effectively eliminated immunosuppressive MDSCs, Tregs, and M2-like macrophages in tumors and promoted the maturation of dendritic cells (DCs) in the draining lymph nodes, resulting in robust and durable systemic antitumor efficacy, with 7 out of 8 mice surviving over 60 days. Our programmable DNA-templated printing technology enables the rational design of multispecific therapeutics with modular composition and function but minimal production issues, providing a versatile tool for the development of multifunctional personalized medicine.