Peptide vaccines offer a direct way to initiate an immunogenic response to a defined antigen epitope. However, peptide vaccines are unstable in vivo, subject to rapid enzymatic proteolysis. Replacement of an α-amino acid residue with a homologous β-amino acid residue (native side chain, but backbone extended by a single CH2 unit) impairs proteolysis at nearby amide bonds. Therefore, antigen analogues containing α-to-β replacements have been examined for functional mimicry of native all-α antigens. Another group previously took this approach in the ovalbumin (OVA) antigen model by evaluating single α-to-β analogues of the murine major histocompatibility complex (MHC) I-restricted peptide SIINFEKL.

We re-examined this set of α/β SIINFEKL antigens. We tested the susceptibility to proteolysis in mouse serum and their ability to activate OVA-antigen-specific CD8 T cells in vitro. Additionally, we tested the α/β antigens in vivo for their ability to induce an antigen-specific immunogenic response in naïve mice and in OVA-expressing tumor-bearing mice.

The α/β antigens were comparable to the native antigen in their susceptibility to proteolysis in serum. Each α/β antigen was capable of activating antigen-specific CD8 T cells in vitro. However, antigen-specific CD8 T cells induced against α/β antigens in vivo were not cross-reactive to the native antigen. Moreover, immunization with α/β analogues did not elicit anti-tumor effects in tumor-bearing mice.

We conclude that even though α/β analogues of the SIINFEKL antigen can elicit a T cell-based response, this class of backbone-modified peptides is not promising from the perspective of antitumor vaccine development.

Currently, autoimmune disorders are predominantly managed with broad-spectrum immunosuppressive agents and monoclonal antibodies, which can alleviate disease symptoms but are rarely curative and are frequently associated with significant adverse effects. Autoreactive B cells play a key role in the pathogenesis of many autoimmune diseases; however, B-cell-depleting therapies such as rituximab have shown limited efficacy in certain autoimmune diseases, primarily due to the persistence of autoreactive B cells within lymphoid tissues and sites of inflammation. Consequently, there is an urgent need for more effective and targeted therapies for patients with severe and refractory autoimmune conditions. In this context, recent advancements in genetic engineering have facilitated the application of cell-based therapies, which have transitioned from oncology to treating autoimmune diseases. Therapies utilizing chimeric antigen receptor (CAR) engineered immune cells have emerged as a promising and potentially curative approach. Clinical trials targeting CD19-expressing B cells in B cell-driven autoimmune diseases, such as systemic lupus erythematosus (SLE), have yielded encouraging results, demonstrating durable remissions in otherwise treatment-resistant cases. In addition, novel strategies are being developed to broaden the therapeutic scope of CAR-based therapies in autoimmunity, including chimeric autoantibody receptor (CAAR)-T cells designed to eliminate autoantigen-specific B cells selectively and CAR-engineered regulatory T cells (CAR-Tregs) aimed at achieving antigen-specific immune modulation and restoration of self-tolerance. Despite these advances, several challenges persist, including short and long-term safety concerns, limited in vivo persistence, and the high costs associated with personalized cell manufacturing. Innovations in CAR design, such as logic-gated CARs, inducible suicide switches, and universal CAR constructs, are under active investigation to enhance safety, control, scalability, and clinical accessibility.

N-acetyltransferase 10 (NAT10) was reported to be associated with the immune microenvironment in several cancers. However, it is not known in pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the roles and mechanisms of NAT10 in tumor malignancy and the tumor microenvironment (TME) in PDAC.

NAT10 expression and its role in tumor progression and clinical prognosis were analyzed using bioinformatics and functional assays. Downstream genes regulated by NAT10 and their underlying mechanisms were explored using acetylated RNA immunoprecipitation, quantitative polymerase chain reaction, RNA immunoprecipitation, and Western blotting. The role and mechanism of NAT10 in the PDAC TME were further explored using bioinformatics, single-cell RNA sequencing, multiplexed immunofluorescence, and flow cytometry. The association between NAT10 and immunotherapeutic response was investigated in a mouse model by inhibiting the programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) axis with a PD-1/PD-L1 binding inhibitor, Naamidine J.

NAT10 was upregulated in PDAC tissues and cell lines, and was associated with poor progression-free survival of PDAC patients. NAT10 promoted tumor progression by enhancing the mRNA stability of laminin β3 (LAMB3) via N4-acetylation modification, thereby activating the focal adhesion kinase (FAK)/extracellular regulated protein kinases (ERK) pathway. NAT10 promoted subcutaneous tumor growth, increased the proportion of exhausted CD8+ T cells (CD8+ Tex), especially the intermediate CD8+ Tex subset, and decreased the proportion of cytotoxic CD8+ T cell (CD8+ Tc) subset in the PDAC TME. Naamidine J treatment significantly enhanced the proportion of CD8+ Tc subset and reduced the proportion of intermediate CD8+ Tex subset in mice bearing subcutaneous tumors with high NAT10 expression. Regarding the regulatory mechanism, NAT10 increased PD-L1 expression and abundance in tumor cells by activating the LAMB3/FAK/ERK pathway, thereby reducing the cytotoxicity of CD8+ T cells. Inhibition of the PD-1/PD-L1 axis with Naamidine J retrieved CD8+ T cell cytotoxicity.

This study proposes a regulatory role of NAT10 in tumor progression and immune microenvironment via the LAMB3/FAK/ERK pathway in PDAC. These findings may favor the selection of candidates who may benefit from immunotherapy, optimize current therapeutic strategies, and improve the clinical prognosis of PDAC patients.

Neoantigens, derived from tumor-specific mutations, are promising targets of cancer immunotherapy by eliciting tumor-specific T-cell responses while sparing normal cells. Accurate neoantigen prediction relies on immunogenomics and immunopeptidomics. Immunogenomics identifies tumor-specific mutations via next-generation sequencing. Immunopeptidomics detects MHC-presented peptides using mass spectrometry. Integrating these two methods enhances prediction accuracy but faces challenges due to tumor heterogeneity, HLA diversity, and immune evasion. Future advancements will focus on dynamic tumor microenvironment monitoring, multi-omics integration, improved computational models and algorithms to refine neoantigen prediction, and developing optimized personalized vaccines.

Solid tumors pose significant therapeutic challenges due to their resistance to conventional treatments and the complexity of the tumor microenvironment. Cell-based immunotherapies offer a promising approach, enabling precise, personalized treatment through immune system modulation. This review explores several emerging cellular therapies for solid tumors, including tumor-infiltrating lymphocytes, T cell receptor-engineered T cells, CAR T cells, CAR natural killer cells, and macrophages. Tumor-infiltrating lymphocytes and their modified versions, T cell receptor-engineered T cells and CAR T cells, provide personalized immune responses, although their effectiveness can be limited by factors like variation in tumor antigens and the suppressive nature of the tumor environment. Natural killer cells engineered with chimeric receptors offer safer, non-major histocompatibility complex-restricted targeting, while modified macrophages exploit their natural ability to enter tumors and reshape the immune landscape. CAR-modified macrophages and macrophages conjugated with drugs are also considered as therapy for solid tumors. The review also examines the implications of autologous versus allogeneic cell sources. Autologous therapies ensure immunologic compatibility but are limited by scalability and manufacturing constraints. Allogeneic approaches offer "off-the-shelf" potential but require gene editing to avoid immune rejection. Integrating synthetic biology, gene editing, and combinatorial strategies will be essential to enhance efficacy and expand the clinical utility of cellular immunotherapies for solid tumors.

Tissue-resident memory T cells (TRMs) reside in peripheral tissues and provide rapid immune defence against local infection and tumours. Tumour-associated TRMs share common tissue-resident features and formation mechanisms, representing some unique subsets of tumour-infiltrating lymphocytes (TILs). However, differences in the tumour microenvironment(TME) and tumour evolution stage result in TRMs exhibiting temporal and spatial heterogeneity of phenotype and function not only at different stages, before and after treatment, but also between tumours originating from different tissues, primary and metastatic cancer, and tumour and adjacent normal tissue. The infiltration of TRMs is often associated with immunotherapy response and favourable prognosis; however, due to different definitions, it has been shown that some subtypes of TRMs can also have a negative impact. Therefore, it is crucial to precisely characterise the TRM subpopulations that can influence the therapeutic efficacy and clinical prognosis of various solid tumours. Here, we review the spatiotemporal heterogeneity of tumour-associated TRMs, as well as the differences in their impact on clinical outcomes. We also explore the relationship between TRMs and immune checkpoint blockade (ICB) and TIL therapy, providing insights into potential new targets and strategies for immunotherapy.

Immunovirotherapy integrates the oncolytic capabilities of viruses with the modulation of the host immune system to establish robust tumor-specific immune responses. Oncolytic viruses (OVs) are natural or engineered viruses that specifically replicate in and lyse tumor cells, triggering inflammation which recruits immune effector cells to the site of infection. These conditions theoretically synergize with immune checkpoint blockade (ICB), which aids in establishing and maintaining tumor-infiltrating CD8 T cells. However, clinical data directly confirming synergy between OV and ICB therapy is limited despite ICB becoming the standard of care for several cancer types. It has been shown that viral immunodominance may limit antitumor T-cell priming and cause the attrition of tumor-specific T cells, limiting long-term therapeutic efficacy. To overcome these barriers, precise incorporation of virally expressed or exogenously administered tumor-associated antigens (TAAs) can synchronize the expansion of both antiviral and antitumor T cells, creating optimal conditions for ICB treatment. This tripartite approach leverages our understanding of antiviral immunity to efficiently expand subdominant antitumor T cells in vivo. In this review, we dissect the fundamental paradigm of immunovirotherapy regarding antiviral inflammation and TAAs, followed by relevant combinatorial strategies employed in preclinical and clinical settings for the treatment of solid tumors.

Anti-PD-1/PD-L1-based immune checkpoint blockade targeting T cell immunoregulatory proteins has revolutionized cancer treatment. However, only a limited number of patients benefit from this therapy due to the therapeutic resistance and inhibitory pathways other than PD-1 in T cells. Here, we report a new strategy to restore and enhance effector T cell functions through nanoparticle-induced synergistic target of immune checkpoints. SHP099, an allosteric inhibitor for Src-homology domain-containing protein tyrosine phosphatase-2 (SHP2), and CPI-444, a selected inhibitor for adenosine A2AR receptor, were co-encapsulated in a T cell-targeting nanoparticle (SCNP/αCD8). SCNP/αCD8 nanoparticles showed preferable internalization by CD8+ T cells and efficiently blocked SHP2 and A2AR signaling pathways. The simultaneous blockade thus enhanced proliferation, cytokine secretion, cytotoxic function and antitumor activity of CD8+ T cells and significantly inhibited tumor growth in the mouse model. The enhanced anti-tumor immunity in vivo is also ascribed to improved infiltration of effector CD8+ T cells in tumor tissues. These findings suggest that concurrent blockade of A2AR and SHP2 immune checkpoint signaling pathways with small molecule inhibitors offers a promising alternative strategy to enhance T cell functions for enhanced cancer immunotherapy.

Developing T-cell or vaccine therapies for pancreatic ductal adenocarcinoma (PDAC) has been challenging because of a lack of knowledge regarding immunodominant, cancer-specific antigens as PDAC are characterized by a scarcity of genomic mutation-associated neoepitopes, and effective approaches to discover them are limited.

An advanced mass spectrometry approach was employed to compare the immunopeptidome of PDAC tissues and matched normal tissues from the same patients.

This study identified HLA class I-binding variant peptides derived from canonical proteins, which had single amino-acid substitutions not attributed to genetic mutations or RNA editing. These amino-acid substitutions appeared to result from translational errors. The variant peptides were predominantly found in tumor tissues, with certain peptides common among multiple patients. Importantly, several of these variant peptides were more immunogenic than their wild-type counterparts.

The shared noncanonical neoepitopes identified in this study offer promising candidates for vaccine and T-cell therapy development, potentially providing new avenues for immunotherapy in PDAC. See related commentary by Yuan et al., p. 1821.

The shared HLA-bound neoepitopes in pancreatic ductal adenocarcinoma (PDAC) represent a novel class of noncanonical antigens with single amino acid substitutions resulting from translational errors. These peptides, shared across patients with PDAC, showed higher immunogenicity than wild-type counterparts, offering potential candidates for specific immunotherapy development in PDAC. See related article by Zhang et al., p. 1956.

Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that TYW2 knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, Tyw2 loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity in vivo. Importantly, reduced TYW2 expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.

T cells play a vital role in the immune system by recognizing and eliminating infected or cancerous cells, thus driving adaptive immune responses. Their activation is triggered by the binding of T cell receptors (TCRs) to epitopes presented on Major Histocompatibility Complex (MHC) molecules. However, experimentally identifying antigens that could be recognizable by T cells and possess immunogenic properties is resource-intensive, with most candidates proving non-immunogenic, underscoring the need for computational tools to predict peptide-MHC (pMHC) and TCR binding. Despite extensive efforts, accurately predicting TCR-antigen binding pairs remains challenging due to the vast diversity of TCRs.

In this study, we propose a Contrastive Cross-attention model for TCR (ConTCR) and pMHC binding prediction. Firstly, the pMHC and TCR sequences are transformed into high-level embedding by pretrained encoders as feature representations. Then, we employ the multi-modal cross-attention to combine the features between pMHC sequences and TCR sequences. Next, based on the contrastive learning strategy, we pretrained the backbone of ConTCR to boost the model's feature extraction ability for pMHC and TCR sequences. Finally, the model is fine-tuned for classification between positive and negative samples.

Based on this advanced strategy, our proposed model could effectively capture the critical information on TCR-pMHC interactions, and the model is visualized by the attention score heatmap for interpretability. ConTCR demonstrates strong generalization in predicting binding specificity for unseen epitopes and diverse TCR repertoires. On independent non-zero-shot test sets, the model achieved AUC-ROC scores of 0.849 and 0.950; on zero-shot test sets, it obtained AUC-ROC scores of 0.830 and 0.938.

Our framework offers a promising solution for improving pMHC-TCR binding prediction and model interpretability. By leveraging the ConTCR model and pMHC-TCR features, we achieve more precise precision than recently advanced models. Overall, ConTCR is a robust tool for predicting pMHC-TCR binding and holds significant promise to advance TCR-based immunotherapies as a valuable artificial intelligence tool. The codes and data used in this study are available at this website.

Translation of the noncoding genome in cancer can generate cryptic (noncanonical) peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer specificity and immunogenicity of noncanonical HLA-I-bound peptides (ncHLAp) are incompletely understood. Using high-resolution immunopeptidomics, we discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Approximately 30% of ncHLAp exhibited cancer-restricted translation, and a substantial subset were shared among patients. Cancer-restricted ncHLAp displayed robust immunogenic potential in a sensitive ex vivo T cell priming platform. ncHLAp-reactive, T cell receptor-redirected T cells exhibited tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that pancreatic cancer harbors cancer-restricted ncHLAp that can be recognized by cytotoxic T cells. Future therapeutic strategies for pancreatic cancer, and potentially other solid tumors, may include targeting cryptic antigens.

Cancer-related deaths continue to rise, largely due to the suboptimal efficacy of current treatments. Fortunately, immunotherapy has emerged as a promising alternative, offering new hope for cancer patients. Among various immunotherapy approaches, targeting tumor-specific antigens (TSAs) has gained particular attention due to its demonstrated success in clinical settings. Despite these advancements, there are still gaps in our understanding of TSAs. Therefore, this review explores the life cycle of TSAs in cancer, the methods used to identify them, and recent advances in TSAs-targeted cancer therapies. Enhancing medical professionals' understanding of TSAs will help facilitate the development of more effective TSAs-based cancer treatments.

The aim of therapeutic cancer vaccines is to induce tumor-specific cellular immune responses. This requires tumor antigens to be efficiently processed and presented by antigen-presenting cells, in particular dendritic cells (DCs). In addition, DCs require maturation to upregulate the surface expression and secretion of T cell costimulatory molecules, which is achieved by co-administration of adjuvants in vaccines. Peptide-based antigen vaccination is an attractive strategy due to the established biocompatibility of peptides as well as the dosing control. To enhance the efficacy of peptide-based vaccines, antigens can be targeted to DCs. Antigen-adjuvant conjugates are known to enhance T cell activation by ensuring DC maturation upon antigen delivery. In this study, we aim to combine these two approaches in a single molecule, and present a DC-targeted antibody fragment-antigen-adjuvant (AAA)-conjugate. We generate the AAA-conjugate through a combination of site-specific sortase-mediated chemoenzymatic ligation and click chemistry. Ex vivo T cell activation assays show enhanced efficacy of the AAA-conjugate compared to non-adjuvanted control conjugates. The in vivo performance of the AAA-conjugate was suboptimal, which we hypothesize to be a consequence of the hydrophobic character of the conjugate. In vivo efficacy was rescued by co-administration of antibody fragment-antigen conjugates and antibody fragment-adjuvant conjugates, in which the antigen and adjuvant were separatedly delivered using two different DC-targeting molecules. In conclusion, this study provides a proof-of-concept for effective in vivo antigen-specific T cell activation by targeted delivery of both antigen and adjuvant to DCs in a single or separate molecule using site-specific protein engineering.

T cells are crucial for immunosurveillance and tumor eradication, with their dysregulation or absence in the tumor microenvironment linked to immunotherapy resistance. In lung adenocarcinoma (LUAD), this resistance is a significant barrier to effective treatment, highlighting the need for robust biomarkers and therapeutic targets to improve clinical outcomes.

T cell-related markers were identified through single-cell RNA sequencing analysis. The TCGA dataset was used for consensus clustering to define molecular subtypes associated with distinct survival outcomes and immune profiles. A T cell-related prognostic signature was developed by integrating LUAD datasets from TCGA, GSE31210, GSE50081, and GSE68465 using 10 machine learning algorithms. Further analysis linked risk scores to immune infiltration and drug sensitivity. The role of a hub gene in CD4+ T cell function and its involvement in tumor immunity was explored through in vitro experiments and molecular biology techniques.

Cluster analysis identified three LUAD subtypes, with cluster1 showing the best prognosis and immune characteristics. A Lasso + PLSRcox-based signature was a significant risk factor for predicting LUAD patient outcomes, outperforming traditional clinicopathological factors. The risk score correlated with immune microenvironment features, immune cell infiltration, and sensitivity to immunotherapy and chemotherapy. CPA3 expression was elevated in activated CD4+ T cells, particularly in Th1 cells, promoting differentiation and IFN-γ secretion. Overexpression of CPA3 enhanced tumor cell apoptosis and increased Granzyme B and IFN-γ levels, highlighting its role in immune responses.

We developed a powerful prognostic signature in LUAD that accurately predicts clinical outcomes and can guide immunotherapy and chemotherapy responses.

Tumor-targeted T cells engineered for targeting and killing tumor cells have revolutionized cancer treatment, specifically in hematologic malignancies, through chimeric antigen receptor (CAR) T cell therapy. However, the migration of this success to lung cancer is challenging due to the tumor microenvironment (TME), antigen heterogeneity, and limitations of T cell infiltration. This review aims to evaluate current strategies addressing these barriers, focusing on the optimization of tumor-associated antigen (TAA) targeting, such as epidermal growth factor receptor (EGFR), mucin-1 (MUC1), and mesothelin (MSLN), which are frequently overexpressed in lung cancer and offer promising targets for CAR T-cell therapy. In this review, we discuss recent progress in CAR T cell engineering, applying enhanced costimulatory molecules, cytokine-secreting CAR T cells, and engineered modifications to improve T cell resilience in immunosuppressive environments. Additionally, this review also evaluates combination therapies of immune checkpoint inhibitors and recently published clinical trials on lung cancer with CAR T cells. We offer insights into the way to optimize CAR T cell therapy for lung cancer by analyzing antigen selection, immune evasion, and the strategies to enhance T cell persistence and tumor infiltration.

Tumor displays various forms of tumor heterogeneity including immune heterogeneity that allow cancer cells to survive during conventional anticancer drug interventions. Thus, there is a strong rationale for overcoming anticancer drug resistance by employing the components of immune cells. Using the immune system to target tumor cells has revolutionized treatment. Recently, significant progress has been achieved at preclinical and clinical levels to benefit cancer patients.

A review of literature from the past ten years across PubMed, Scopus, and Web of Science focused on immunotherapy strategies. These include immune checkpoint inhibitors (ICIs), tumor-infiltrating lymphocyte therapy, antibody-drug conjugates (ADCs), cancer vaccines, CAR T-cell therapy, and the role of the gut microbiome.

While immunotherapy outcomes have improved, particularly for tumor types such as melanoma and non-small cell lung cancer (NSCLC), challenges persist regarding predictive biomarker identification and better management. Ongoing research on modifiers of immune function like gut microbiome-derived metabolites, next-generation ADCs, and new classes of biologics is warranted. Overall, continued investigation toward optimizing synergistic immunotherapeutic combinations through strategic drug delivery systems is imperative for preclinical and clinical success in cancer patients.

The cell surface proteome, or surfaceome, is the hub for cells to interact and communicate with the outside world. Many disease-associated changes are hard-wired within the surfaceome, yet approved drugs target less than 50 cell surface proteins. In the past decade, the proteomics community has made significant strides in developing new technologies tailored for studying the surfaceome in all its complexity. In this review, we first dive into the unique characteristics and functions of the surfaceome, emphasizing the necessity for specialized labeling, enrichment, and proteomic approaches. An overview of surfaceomics methods is provided, detailing techniques to measure changes in protein expression and how this leads to novel target discovery. Next, we highlight advances in proximity labeling proteomics (PLP), showcasing how various enzymatic and photoaffinity proximity labeling techniques can map protein-protein interactions and membrane protein complexes on the cell surface. We then review the role of extracellular post-translational modifications, focusing on cell surface glycosylation, proteolytic remodeling, and the secretome. Finally, we discuss methods for identifying tumor-specific peptide MHC complexes and how they have shaped therapeutic development. This emerging field of neo-protein epitopes is constantly evolving, where targets are identified at the proteome level and encompass defined disease-associated PTMs, complexes, and dysregulated cellular and tissue locations. Given the functional importance of the surfaceome for biology and therapy, we view surfaceomics as a critical piece of this quest for neo-epitope target discovery.

Currently, there exist two approaches to the treatment of malignant neoplasms: the Karanahan technology and in situ vaccination, which are based on chronometric delivery of therapeutic agents to the tumor depending on the characteristics of tumor cells, as well as the immune status. The main purpose of this study was to experimentally prove the feasibility of combining the Karanahan technology and in situ vaccination with αOX40 antibodies into a single therapeutic platform to achieve a potent additive antitumor therapeutic effect.

BALB/c mice grafted with B-cellular lymphoma A20 were treated using the Karanahan technology consisting of intraperitoneal cyclophosphamide administrations and intratumoral DNA injections according to an individually determined therapeutic regimen, together with in situ vaccination with αOX40. A pathomorphological analysis of the organs of experimental animals that died during the initial attempt to combine the two technologies was carried out. An analysis of blood cell populations was performed to determine the safe time for antibody administration: the number of immune cells capable of activating systemic inflammation (CD11b+Ly-6C+, CD11b+Ly-6G+, CD3-NKp46+CD11b+), the presence of Fc receptor and OX40 on the surface of these cells, and the number of neutrophils activated to NETosis were analyzed. Based on the analysis results, the antitumor efficacy of various modes of combining the Karanahan technology and in situ vaccination was studied.

When αOX40 was administered 5 h after each treatment using the Karanahan technology, mass death of mice caused by systemic inflammation and multiple organ failure was observed. The state of blood cells after the treatment using the Karanahan technology at the time points corresponding to antibody injections was analyzed to elucidate the reasons for this effect. It was found that at some time points, there occurs activation of the immune system and a powerful release (up to 16%) of monocytes and granulocytes carrying Fc receptor and OX40 on their surface into blood; when interacting with αOX40, they can activate the lytic potential of these cells. Activation of neutrophils to NETosis was also observed. Based on these findings, a study was carried out in different time regimes to combine the Karanahan technology and αOX40 injections. When αOX40 was injected into the points of minimal release of myeloid cells into the blood, increased survival rate and the greatest antitumor efficacy were observed: 37% of animals survived without relapses on day 100 after experiment initiation. Conclusions: The results obtained indicate that it is possible to combine the Karanahan technology and in situ vaccination with αOX40, with obligatory constant monitoring of the number of myeloid cells in peripheral blood to determine the safe time for antibody injection.

Sarcomas are a heterogeneous group of malignancies with limited therapeutic options, particularly in the metastatic setting. Adoptive cellular therapies (ACTs), including tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR) gene-modified T-cell therapy, offer promising novel approaches for these refractory tumors. TIL-based therapy has demonstrated early efficacy in melanoma and myeloma, with ongoing trials exploring its role in sarcoma. CAR T-cell strategies targeting HER2, GD2, and B7-H3 antigens are in development, though challenges such as tumor microenvironment-mediated resistance and antigen escape remain significant. Engineered TCRs, particularly those targeting MAGE-A4 and NY-ESO-1, have shown promising clinical results in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), leading to the recent FDA approval of afamitresgene autoleucel (afami-cel) and letetresgene autoleucel (lete-cel). Despite encouraging preliminary data, ACT implementation faces barriers including limited antigen specificity, off-tumor toxicity, immune evasion, and manufacturing scalability. Future research will focus on optimizing lymphodepleting regimens, mitigating toxicity, enhancing in vivo persistence, and combining ACT with other therapeutic agents. As clinical trials expand, ACT holds the potential to revolutionize sarcoma treatment by offering durable, targeted therapies for previously refractory disease.

Background: In recent years, tumor vaccines have demonstrated unexpected success in cancer treatment. However, it still faces several challenges, including insufficient antigen and adjuvant delivery, unsuitable antigen delivery system, and inadequate antigen-presenting cell (APC) maturation. Antigenic adjuvant co-delivery tactics could be one way to enhance APC maturation. Methods: Membrane-fused nanovesicles were synthesized by separating melanoma cell membranes from BCG cytoplasmic membranes. Dynamic light scattering and transmission electron microscopy were used for measuring the vesicles' size and shape. The uptake of vesicles by mouse bone marrow-derived dendritic cells and the activation of DC cells by vesicles were verified in vitro. In order to further confirm the material's capacity to activate the immune system and its ability to inhibit tumor growth, the activation of DC and T cells in mouse draining lymph nodes and the concentration of anti-tumor cytokines were measured. Results: The hybrid vesicles were homogeneous in size and could facilitate phagocytosis by dendritic cells (DCs). They could also effectively activate DCs and T cells in vitro and in vivo, eliciting anti-tumor immunity. Moreover, the vesicles demonstrated satisfying biosafety with no major side effects. Conclusions: Motivated by the myth of the Trojan Horse, we created an antigen-adjuvant-integrated nanovesicle that merges the BCG cytomembrane with the tumor cell membrane, which can achieve immune cell stimulation and tumor antigen delivery simultaneously. In conclusion, these findings support the potential application of dual-membrane fusion nanovesicles as tumor vaccines.

In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 .

As the seventh-leading contributor to global cancer-related deaths, esophageal cancer (EC) is one of the most challenging types of cancer. Despite advancements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the five-year survival rate remains low, underscoring the need for the development of more efficacious treatment approaches. Immunotherapy has emerged as a promising treatment approach, offering new hope for EC patients. This review provides an in-depth examination of the latest immunotherapeutic strategies for EC, focusing on immune checkpoint inhibitors, adoptive cell therapy, cancer vaccines, and oncolytic virotherapy. We critically analyze the current clinical data to highlight the progress and pitfalls of each immunotherapeutic approach for EC. Additionally, we explore the potential for combination therapies, which could overcome the resistance often seen with monotherapies. Finally, we discuss the limitations of current treatments and outline key areas for future research to improve patient outcomes and survival.

Over the past few decades, cancer immunotherapy has experienced a significant revolution due to the advancements in immune checkpoint inhibitors (ICIs) and adoptive cell therapies (ACTs), along with their regulatory approvals. In recent times, there has been hope in the effectiveness of cancer vaccines for therapy as they have been able to stimulate de novo T-cell reactions against tumor antigens. These tumor antigens include both tumor-associated antigen (TAA) and tumor-specific antigen (TSA). Nevertheless, the constant quest to fully achieve these abilities persists. Therefore, this review offers a broad perspective on the existing status of cancer immunizations. Cancer vaccine design has been revolutionized due to the advancements made in antigen selection, the development of antigen delivery systems, and a deeper understanding of the strategic intricacies involved in effective antigen presentation. In addition, this review addresses the present condition of clinical tests and deliberates on their approaches, with a particular emphasis on the immunogenicity specific to tumors and the evaluation of effectiveness against tumors. Nevertheless, the ongoing clinical endeavors to create cancer vaccines have failed to produce remarkable clinical results as a result of substantial obstacles, such as the suppression of the tumor immune microenvironment, the identification of suitable candidates, the assessment of immune responses, and the acceleration of vaccine production. Hence, there are possibilities for the industry to overcome challenges and enhance patient results in the coming years. This can be achieved by recognizing the intricate nature of clinical issues and continuously working toward surpassing existing limitations.

The impact of Helicobacter pylori (H. pylori) status on gastric cancer survival remains unclear. In this study, we conducted a prognostic analysis of 488 gastric cancer patients and performed single-cell RNA sequencing (scRNA-seq) on 18,717 T cells from six tumor samples with varying H. pylori statuses. Our findings revealed that gastric cancer patients with H. pylori infection had significantly longer survival times compared to those with negative H. pylori status. After unsupervised re-clustering of T cells based on scRNA-seq data, we identified ten CD4+ and twelve CD8+ clusters. Among them, four CD8+ T cell clusters exhibited distinct distributions based on H. pylori infection status. One cluster, marked by CXCL13, showed high levels of IFNG and GZMB in H. pylori-infected patients, while another cluster, which expressed immune suppression related genes like AREG and PTGER2, was predominantly comprised of cells from non-infected patients. High PTGER2 expression was significantly associated with worse prognosis in patients with high CD8 expression. These insights advance our understanding of H. pylori's influence on T cell responses in gastric cancer, aiding in treatment and prognostic strategies.

Dendritic cells (DCs) act as a bridge between innate and adaptive immunity by presenting antigens to effector immune cells and have shown broad application potential in tumor immunotherapy. However, the clinical translation of DC vaccines encounters significant challenges, such as the immunosuppressive tumor microenvironment (TME) and the sub-optimal DC function and vaccine efficacy in vivo. In this review, our investigation has uncovered the latest developments in DC vaccines and their potential in cancer immunotherapy, with a special emphasis on the integration of nanotechnology. Several types of nanomaterials, including protein cage nanoparticles (NPs), biomimetic NPs, and targeted multifunctional NPs, have been developed to enhance the antigen presentation ability of DCs and their stimulatory effects on T cells. In addition, we have also summarized the synergistic anti-cancer effects of DC vaccines with immune checkpoint inhibitors, chemotherapy, and radiotherapy. In addition, recent advances in nanotechnology have made it possible to develop novel biomarkers that can enhance the antigen presentation capacity of DCs and stimulate T cells. These biomarkers not only improve the accuracy and precision of DC vaccine design but also provide new insights into understanding the mechanisms of the DC-mediated immune response. Despite challenges pertaining to technical complexities and individual adaptation in the design and production of DC vaccines, personalized immunotherapy based on DCs is expected to become an important part of cancer treatment with rapid developments in biotechnology and immunology. This review provides new perspectives and potential solutions for the optimal design and application of DC vaccines in cancer therapy.

Immune cells are sensitive to the perception of mechanical stimuli in the tumor microenvironment. Changes in biophysical cues within tumor tissue can alter the force-sensing mechanisms experienced by cells. Mechanical stimuli within the extracellular matrix are transformed into biochemical signals through mechanotransduction. Delving into how these minute biophysical cues affect the activation of immune cells, metabolic reprogramming, and subsequent effector functions could offer perspectives on therapeutic interventions for immune-related disorders. Our study used a ternary phycocyanin-podophyllotoxin-IDO1 self-assembled nanoplatform to investigate molecule-scale regulation of mechanical cues in the tumor microenvironment on immune cell functions to modulate immune responses. After treatment, a caspase cascade was mediated by remodeling mechanical cues, including cytoskeleton-related assembly, force channel activation, and metabolic reprogramming, all of which contributed to enhancing anti-tumor immunity via mechanotransduction. The results will be helpful for understanding the interaction between cell force remodeling and antitumor immunity via mechanotransduction.

Cancer remains a leading cause of mortality globally. Recent improvements in survival have been facilitated by the development of targeted and less toxic immunotherapies, such as chimeric antigen receptor (CAR)-T cells and antibody-drug conjugates (ADCs). These therapies, effective in treating both pediatric and adult patients with solid and hematological malignancies, rely on the identification of cancer-specific surface protein targets. While technologies like RNA sequencing and proteomics exist to survey these targets, identifying optimal targets for immunotherapies remains a challenge in the field.

To address this challenge, we developed ImmunoTar, a novel computational tool designed to systematically prioritize candidate immunotherapeutic targets. ImmunoTar integrates user-provided RNA-sequencing or proteomics data with quantitative features from multiple public databases, selected based on predefined criteria, to generate a score representing the gene's suitability as an immunotherapeutic target. We validated ImmunoTar using three distinct cancer datasets, demonstrating its effectiveness in identifying both known and novel targets across various cancer phenotypes. By compiling diverse data into a unified platform, ImmunoTar enables comprehensive evaluation of surface proteins, streamlining target identification and empowering researchers to efficiently allocate resources, thereby accelerating the development of effective cancer immunotherapies.

Code and data to run and test ImmunoTar are available at https://github.com/sacanlab/immunotar.

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes across several solid tumour types. Prominent efforts have focused on understanding the anticancer mechanisms of these agents, identifying biomarkers of response and uncovering resistance mechanisms to develop new immunotherapeutic approaches. This research has underscored the crucial roles of the tumour microenvironment and, particularly, tumour-infiltrating lymphocytes (TILs) in immune-mediated tumour elimination. Numerous studies have evaluated the prognostic and predictive value of TILs and the mechanisms that govern T cell dysfunction, fuelled by technical developments in single-cell transcriptomics, proteomics, high-dimensional spatial platforms and advanced computational models. However, questions remain regarding the definition of TILs, optimal strategies to study them, specific roles of different TIL subpopulations and their clinical implications in different treatment contexts. Additionally, most studies have focused on the abundance of major TIL subpopulations but have not developed standardized quantification strategies or analysed other crucial aspects such as their functional profile, spatial distribution and/or arrangement, tumour antigen-reactivity, clonal diversity and heterogeneity. In this Review, we discuss a conceptual framework for the systematic study of TILs and summarize the evidence regarding their biological properties and biomarker potential for ICI therapy. We also highlight opportunities, challenges and strategies to support future developments in this field.

Tumor vaccines have become a crucial strategy in cancer immunotherapy. Challenges of traditional tumor vaccines include inadequate immune activation and low efficacy of antigen delivery. Nanoparticles, with their tunable properties and versatile functionalities, have redefined the landscape of tumor vaccine design. In this review, we outline the multifaceted roles of nanoparticles in tumor vaccines, ranging from their capacity as delivery vehicles to their function as immunomodulatory adjuvants capable of stimulating anti-tumor immunity. We discuss how this innovative approach significantly boosts antigen presentation by leveraging tailored nanoparticles that facilitate efficient uptake by antigen-presenting cells. These nanoparticles have been meticulously designed to overcome biological barriers, ensuring optimal delivery to lymph nodes and effective interaction with the immune system. Overall, this review highlights the transformative power of nanotechnology in redefining the principles of tumor vaccines. The intent is to inform more efficacious and precise cancer immunotherapies. The integration of these advanced nanotechnological strategies should unlock new frontiers in tumor vaccine development, enhancing their potential to elicit robust and durable anti-tumor immunity.

T cells have a critical role in mediating antitumour immunity. The success of immune checkpoint inhibitors (ICIs) for cancer treatment highlights how enhancing endogenous T cell responses can mediate tumour regression. However, mortality remains high for many cancers, especially in the metastatic setting. Based on advances in the genetic characterization of tumours and identification of tumour-specific antigens, individualized therapeutic cancer vaccines targeting mutated tumour antigens (neoantigens) are being developed to generate tumour-specific T cells for improved therapeutic responses. Early clinical trials using individualized neoantigen vaccines for patients with advanced disease had limited clinical efficacy despite demonstrated induction of T cell responses. Therefore, enhancing T cell activity by improving the magnitude, quality and breadth of T cell responses following vaccination is one current goal for improving outcome against metastatic tumours. Another major consideration is how T cells can be further optimized to function within the tumour microenvironment (TME). In this Perspective, we focus on neoantigen vaccines and propose a new approach, termed Vax-Innate, in which vaccination through intravenous delivery or in combination with tumour-targeting immune modulators may improve antitumour efficacy by simultaneously increasing the magnitude, quality and breadth of T cells while transforming the TME into a largely immunostimulatory environment for T cells.

Understanding the status and function of tumor-infiltrating immune cells is essential for improving immunotherapeutic effects and predicting the clinical response in human patients with carcinoma. However, little is known about tumor-infiltrating immune cells, and the corresponding research results in hepatocellular carcinoma (HCC) are limited.

To investigate potential biomarker genes that are important for the development of HCC and to understand how immune cell subsets react throughout this process.

Using single-cell RNA sequencing and T-cell receptor sequencing, the heterogeneity and potential functions of immune cell subpopulations from HCC tissue and normal tissue adjacent to carcinoma, as well as their possible interactions, were analyzed.

Eight T-cell clusters from patients were analyzed and identified using bioinformatics, including six typical major T-cell clusters and two newly identified T-cell clusters, among which Fc epsilon receptor 1G+ T cells were characterized by the upregulation of Fc epsilon receptor 1G, tyrosine kinase binding protein, and T cell receptor delta constant, whereas metallothionein 1E+ T cells proliferated significantly in tumors. Differentially expressed genes, such as regulator of cell cycle, cysteine and serine rich nuclear protein 1, SMAD7 and metallothionein 1E, were identified as significantly upregulated in tumors and have potential as biomarkers. In association with T-cell receptor analysis, we inferred the clonal expansion characteristics of each T-cell cluster in HCC patients.

We identified lymphocyte subpopulations and potential biomarker genes critical for HCC development and revealed the clonal amplification of infiltrating T cells. These data provide valuable resources for understanding the response of immune cell subsets in HCC.

Merkel Cell Carcinoma (MCC) is an uncommon yet highly malignant form of skin cancer, frequently linked to the Merkel cell polyomavirus (MCPyV). This review comprehensively covers data from year 2000 to 2024, employing keywords such as MCC, MCPyV Oncoproteins, Immunohistochemistry, Southern Blot, Western Blot, Polymerase Chain Reaction (PCR), Digital Droplet PCR (ddPCR), Next-Generation Sequencing (NGS), and In Situ Hybridization (ISH). The search engines utilized were Google, PubMed Central, Scopus, and other journal databases like ScienceDirect. This review is essential for researchers and the broader medical community as it consolidates two decades of research on the genetic and molecular profiling of MCC, particularly focusing on MCPyV's role in its pathogenesis. It highlights the diagnostic advancements and therapeutic potential of targeting viral oncoproteins and provides insights into the development of both in vivo and in vitro models for better understanding MCC. The findings emphasize the significance of early detection, molecular diagnostics, and personalized treatment approaches, aiming to improve outcomes for patients with this malignant malignancy.