Target For Cancer Immunotherapy Research Articles

Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine.

Accumulating evidence indicates that aberrant signalling stemming from genetic abnormalities in cancer cells has a fundamental role in their evasion of antitumour immunity. Immune escape mechanisms include enhanced expression of immunosuppressive molecules, such as immune-checkpoint proteins, and the accumulation of immunosuppressive cells, including regulatory T (Treg) cells, in the tumour microenvironment. Therefore, Treg cells are key targets for cancer immunotherapy. Given that therapies targeting molecules predominantly expressed by Treg cells, such as CD25 or GITR, have thus far had limited antitumour efficacy, elucidating how certain characteristics of cancer, particularly genetic abnormalities, influence Treg cells is necessary to develop novel immunotherapeutic strategies. Hence, Treg cell-targeted strategies based on the particular characteristics of cancer in each patient, such as the combination of immune-checkpoint inhibitors with molecularly targeted agents that disrupt the immunosuppressive networks mediating Treg cell recruitment and/or activation, could become a new paradigm of cancer therapy. In this Review, we discuss new insights on the mechanisms by which cancers generate immunosuppressive networks that attenuate antitumour immunity and how these networks confer resistance to cancer immunotherapy, with a focus on Treg cells. These insights lead us to propose the concept of 'immuno-genomic precision medicine' based on specific characteristics of cancer, especially genetic profiles, that correlate with particular mechanisms of tumour immune escape and might, therefore, inform the optimal choice of immunotherapy for individual patients.

Long non-coding RNAs in cancer: multifaceted roles and potential targets for immunotherapy.

Cancer remains a major global health concern with high mortality rates mainly due to late diagnosis and poor prognosis. Long non-coding RNAs (lncRNAs) are emerging as key regulators of gene expression in human cancer, functioning through various mechanisms including as competing endogenous RNAs (ceRNAs) and indirectly regulating miRNA expression. LncRNAs have been found to have both oncogenic and tumor-suppressive roles in cancer, with the former promoting cancer cell proliferation, migration, invasion, and poor prognosis. Recent research has shown that lncRNAs are expressed in various immune cells and are involved in cancer cell immune escape and the modulation of the tumor microenvironment, thus highlighting their potential as targets for cancer immunotherapy. Targeting lncRNAs in cancer or immune cells could enhance the anti-tumor immune response and improve cancer immunotherapy outcomes. However, further research is required to fully understand the functional roles of lncRNAs in cancer and the immune system and their potential as targets for cancer immunotherapy. This review offers a comprehensive examination of the multifaceted roles of lncRNAs in human cancers, with a focus on their potential as targets for cancer immunotherapy. By exploring the intricate mechanisms underlying lncRNA-mediated regulation of cancer cell proliferation, invasion, and immune evasion, we provide insights into the diverse therapeutic applications of these molecules.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 μM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

Tumour-associated neutrophils: Potential therapeutic targets in pancreatic cancer immunotherapy.

Pancreatic cancer (PC) is a highly malignant tumour of the digestive system with poor therapeutic response and low survival rates. Immunotherapy has rapidly developed in recent years and has achieved significant outcomes in numerous malignant neoplasms. However, responses to immunotherapy in PC are rare, and the immunosuppressive and desmoplastic tumour microenvironment (TME) significantly hinders their efficacy in PC. Tumour-associated neutrophils (TANs) play a crucial role in the PC microenvironment and exert a profound influence on PC immunotherapy by establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current status of PC immunotherapy. The present review aims to offer a comprehensive summary of the latest progress in understanding the involvement of TANs in PC desmoplastic and immunosuppressive functions and to emphasise the potential therapeutic implications of focusing on TANs in the immunotherapy of this deleterious disease. Finally, we provide an outlook for the future use of TANs in PC immunotherapy.

Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy.

The Stimulator of Interferon Genes (STING) pathway is a promising target for cancer immunotherapy. Despite recent advances, therapies targeting the STING pathway are often limited by routes of administration, suboptimal STING activation, or off-target toxicity. Here, we report a dendritic cell (DC)-targeted polymeric prodrug platform (polySTING) that is designed to optimize intracellular delivery of a diamidobenzimidazole (diABZI) small-molecule STING agonist while minimizing off-target toxicity after parenteral administration. PolySTING incorporates mannose targeting ligands as a comonomer, which facilitates its uptake in CD206+/mannose receptor+ professional antigen-presenting cells (APCs) in the tumor microenvironment (TME). The STING agonist is conjugated through a cathepsin B-cleavable valine-alanine (VA) linker for selective intracellular drug release after receptor-mediated endocytosis. When administered intravenously in tumor-bearing mice, polySTING selectively targeted CD206+/mannose receptor+ APCs in the TME, resulting in increased cross-presenting CD8+ DCs, infiltrating CD8+ T cells in the TME as well as maturation across multiple DC subtypes in the tumor-draining lymph node (TDLN). Systemic administration of polySTING slowed tumor growth in a B16-F10 murine melanoma model as well as a 4T1 murine breast cancer model with an acceptable safety profile. Thus, we demonstrate that polySTING delivers STING agonists to professional APCs after systemic administration, generating efficacious DC-driven antitumor immunity with minimal side effects. This new polymeric prodrug platform may offer new opportunities for combining efficient targeted STING agonist delivery with other selective tumor therapeutic strategies.

Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-positive Breast Cancer.

Estrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.

Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an extracellular enzyme responsible for hydrolyzing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), the endogenous agonist for the stimulator of interferon genes (STING) pathway. Inhibition of ENPP1 can trigger STING and promote antitumor immunity, offering an attractive therapeutic target for cancer immunotherapy. Despite progress in the discovery of ENPP1 inhibitors, the diversity in chemical structures and the efficacy of the agents are far from desirable, emphasizing the demand for novel inhibitors. Herein, we describe the design, synthesis, and biological evaluation of a series of ENPP1 inhibitors based on the pyrido[2,3-d]pyrimidin-7-one scaffold. Optimization efforts led to compound 31 with significant potency in both ENPP1 inhibition and STING pathway stimulation in vitro. Notably, 31 demonstrated in vivo efficacy in a syngeneic 4T1 mouse triple negative breast cancer model. These findings provide a promising lead compound with a novel scaffold for further drug development in cancer immunotherapy.

Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy.

Notch signaling pathway is a highly conserved system of cell-to-cell communication that participates in various biological processes, such as stem cell maintenance, cell fate decision, cell proliferation and death during homeostasis and development. Dysregulation of Notch signaling has been associated with many aspects of cancer biology, such as maintenance of cancer stem-like cells (CSCs), cancer cell metabolism, angiogenesis and tumor immunity. Particularly, Notch signaling can regulate antitumor or pro-tumor immune cells within the tumor microenvironment (TME). Currently, Notch signaling has drawn significant attention in the therapeutic development of cancer treatment. In this review, we focus on the role of Notch signaling pathway in remodeling tumor immune microenvironment. We describe the impact of Notch signaling on the efficacy of cancer immunotherapies. Furthermore, we summarize the results of relevant preclinical and clinical trials of Notch-targeted therapeutics and discuss the challenges in their clinical application in cancer therapy. An improved understanding of the involvement of Notch signaling in tumor immunity will open the door to new options in cancer immunotherapy treatment.

Stem cells in disguise.

Epitope editing can empower targeted cancer immunotherapies.

PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy.

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.

Complement factor H: a novel innate immune checkpoint in cancer immunotherapy.

The elimination of cancer cells critically depends on the immune system. However, cancers have evolved a variety of defense mechanisms to evade immune monitoring, leading to tumor progression. Complement factor H (CFH), predominately known for its function in inhibiting the alternative pathway of the complement system, has recently been identified as an important innate immunological checkpoint in cancer. CFH-mediated immunosuppression enhances tumor cells' ability to avoid immune recognition and produce an immunosuppressive tumor microenvironment. This review explores the molecular underpinnings, interactions with immune cells, clinical consequences, and therapeutic possibilities of CFH as an innate immune checkpoint in cancer control. The difficulties and opportunities of using CFH as a target in cancer immunotherapy are also explored.

Tumor Burden Dictates the Neoantigen Features Required to Generate an Effective Cancer Vaccine.

Tumor neoantigens (nAg) represent a promising target for cancer immunotherapy. The identification of nAgs that can generate T-cell responses and have therapeutic activity has been challenging. Here, we sought to unravel the features of nAgs required to induce tumor rejection. We selected clinically validated Great Ape-derived adenoviral vectors (GAd) as a nAg delivery system for differing numbers and combinations of nAgs. We assessed their immunogenicity and efficacy in murine models of low to high disease burden, comparing multi-epitope versus mono-epitope vaccines. We demonstrated that the breadth of immune response is critical for vaccine efficacy and having multiple immunogenic nAgs encoded in a single vaccine improves efficacy. The contribution of each single neoantigen was examined, leading to the identification of 2 nAgs able to induce CD8+ T cell-mediated tumor rejection. They were both active as individual nAgs in a setting of prophylactic vaccination, although to different extents. However, the efficacy of these single nAgs was lost in a setting of therapeutic vaccination in tumor-bearing mice. The presence of CD4+ T-cell help restored the efficacy for only the most expressed of the two nAgs, demonstrating a key role for CD4+ T cells in sustaining CD8+ T-cell responses and the necessity of an efficient recognition of the targeted epitopes on cancer cells by CD8+ T cells for an effective antitumor response. This study provides insight into understanding the determinants of nAgs relevant for effective treatment and highlights features that could contribute to more effective antitumor vaccines. See related Spotlight by Slingluff Jr, p. 382.

Mechanistic regulation of HERV activation in tumors and implications for translational research in oncology.

Transcription of distinct loci of human endogenous retroviruses (HERVs) and in some cases, translation of these transcripts have been consistently observed in many types of cancer. It is still debated whether HERV activation serves as a trigger for carcinogenesis or rather occurs as a consequence of epigenetic alterations and other molecular sequelae that characterize cellular transformation. Here we review the known molecular and epigenetic mechanisms of HERV activation in cancer cells as well as its potential contribution to carcinogenesis. Further, we describe the use of HERV expression in cancer diagnostic and characterize the potential of HERV-derived antigens to serve as novel targets for cancer immunotherapy. We believe this review, which summarizes both what is known as well as unknown in this rapidly developing field, will boost interest in research on the therapeutic potential of targeting HERV elements in tumors and the impact of HERV activation in oncogenesis.

Unveiling the structural mechanisms of nonpeptide ligand recognition and activation in human chemokine receptor CCR8.

The human CC chemokine receptor 8 (CCR8) is an emerging therapeutic target for cancer immunotherapy and autoimmune diseases. Understanding the molecular recognition of CCR8, particularly with nonpeptide ligands, is valuable for drug development. Here, we report three cryo-electron microscopy structures of human CCR8 complexed with Gi trimers in the ligand-free state or activated by nonpeptide agonists LMD-009 and ZK 756326. A conserved Y1.39Y3.32E7.39 motif in the orthosteric binding pocket is shown to play a crucial role in the chemokine and nonpeptide ligand recognition. Structural and functional analyses indicate that the lack of conservation in Y1143.33 and Y1724.64 among the CC chemokine receptors could potentially contribute to the selectivity of the nonpeptide ligand binding to CCR8. These findings present the characterization of the molecular interaction between a nonpeptide agonist and a chemokine receptor, aiding the development of therapeutics targeting related diseases through a structure-based approach.

The prognostic value and potential immunotherapeutic efficacy of ACVR1 in treating gastric cancer.

The discovery of biomarkers has facilitated the treatment of cancer. At present, the relationship between activin A receptor type-1 (ACVR1) and gastric cancer is gradually discovered. The aim of this study was to explore the expression of ACVR1 in gastric cancer and its clinical significance, to study the relationship between ACVR1 and tumor microenvironment (TME) for the prognosis of gastric cancer, and to further identify new targets for immunotherapy in gastric cancer. ACVR1 was first selected as a study gene according to several cancer and gastric cancer public datasets. Its pancancer expression was explored using the UCSC Xena database. The expression level, prognosis, and clinicopathological features of ACVR1 in gastric cancer were analyzed using The Cancer Genome Atlas (TCGA) database. Immunohistochemistry (IHC)-based experiments were conducted to study the expression of ACVR1 at the protein level. The IHC data were analyzed for correlations between ACVR1 expression and various clinicopathological factors and prognosis. The correlation of this gene with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, immune infiltration, immune checkpoints, drug therapy, tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) system was analyzed using R software. TCGA data showed that the expression of ACVR1 was higher in gastric cancer tissues than in paracancerous tissues. Moreover, the IHC experiments indicated that ACVR1 was upregulated in gastric cancer tissues at the protein level. Both univariate Cox and multivariate Cox results showed that the increase of ACVR1 was closely associated with tumor stage, size, lymph node metastasis, and age. High ACVR1 expression was linked to a poor prognosis of gastric cancer. The results also revealed that ACVR1 was closely related to suppressive immune cells and pathways. Analyses of immune checkpoints, antitumor drug, TMB, and immune microenvironment indicated that ACVR1 had an antitumor immune effect, promoting gastric cancer development and leading to poor immunotherapy. High ACVR1 expression can be used as an independent prognostic factor to predict the prognostic survival of patients with gastric cancer. ACVR1 expression in gastric cancer tissues was significantly correlated with immune infiltration and may thus serve as a potential therapeutic target for gastric cancer immunotherapy.

Abstract B027: Molecular characterization and therapeutic approaches for VISTA+ triple-negative breast cancers

Abstract Introduction: VISTA (V-domain Ig suppressor of T cell activation) is a single-pass transmembrane immune checkpoint receptor that is an emerging clinical target for cancer immunotherapy. Although VISTA confers quiescence to naïve T cells, molecular mechanisms responsible for this effect remain unclear. Also, the effects of VISTA expression on tumor cells remains poorly defined. Methods: Multi-omic profiling was performed in human breast cancer cells lines to determine immune regulatory genes. Human triple-negative breast cancers (N=248) were examined by immunohistochemistry for expression of VISTA, PDL1, PD1 and FoxP3. VISTA expression was engineered into human and mouse triple-negative breast cancer cell lines and growth was characterized in vitro and in mouse models. Membrane receptor trafficking and localization of EGFR and clathrin adapters was performed in cells expressing VISTA, VISTA mutants and VISTA knockouts. Proximity biotinylation identified protein partners that interacted with VISTA’s intracellular domain. Deletion mutagenesis was performed to identify functional VISTA cytoplasmic motifs. Cytokine response and tumor growth kinetics were measured in TNBC mouse models expressing VISTA or VISTA mutants. Results: A class of human triple-negative breast cancers were identified with high VISTA expression, low tumor infiltrating lymphocytes and low proliferative index (8-20% of all TNBCs). Tumor models demonstrated that enforced expression of VISTA in tumor cells caused growth suppression, even in the absence of an immune system. This effect was mapped to the cytoplasmic domain of VISTA, which lacks defined signaling domains. Through biochemical approaches, the clathrin-adaptor molecules NUMB and GULP1 were found in complex with a VISTA intracellular NPGF motif. This motif sequestered NUMB at early endosomes, resulting in diminished NUMB recycling for EGFR endocytosis, thereby causing growth suppression. VISTA impaired NUMB recycling by blocking Rab11 effector complex formation. VISTA NPGF mutations did not disrupt cytokine secretion in mixed lymphocyte assays. VISTA-targeted antibodies did not disrupt NUMB sequestration. VISTA+ tumors were selectively sensitive to VISTA-blocking antibodies. Conclusions: VISTA+ TNBC have distinct features including slower proliferative index and increased sensitivity to VISTA-blocking antibodies. This work identifies mechanisms by which VISTA enforces a quiescent cellular state by sequestering clathrin adapter proteins away from sites of endocytosis in cancer cells. This is the first description of intracellular molecular mechanisms controlled by VISTA’s intracellular tail. It may inform features of the VISTA-dependent immune checkpoint that could be exploited to improve anti-tumor immunity. Integration of these findings with ongoing VISTA clinical trials will be discussed. Citation Format: Joshua Gruber, Yan Zhao, Fatima Charles, Priyanka Reddy, Kristina Paul, Virginia Ezenwa, Marisa Juntilla, Idit Sagiv-Barfi, Yan Peng, Song Zhang, Allison Kurian, Michael Snyder. Molecular characterization and therapeutic approaches for VISTA+ triple-negative breast cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B027.

NF-κB: Governing Macrophages in Cancer.

Tumor-associated macrophages (TAMs) are the major component of the tumor microenvironment (TME), where they sustain tumor progression and or-tumor immunity. Due to their plasticity, macrophages can exhibit anti- or pro-tumor functions through the expression of different gene sets leading to distinct macrophage phenotypes: M1-like or pro-inflammatory and M2-like or anti-inflammatory. NF-κB transcription factors are central regulators of TAMs in cancers, where they often drive macrophage polarization toward an M2-like phenotype. Therefore, the NF-κB pathway is an attractive therapeutic target for cancer immunotherapy in a wide range of human tumors. Hence, targeting NF-κB pathway in the myeloid compartment is a potential clinical strategy to overcome microenvironment-induced immunosuppression and increase anti-tumor immunity. In this review, we discuss the role of NF-κB as a key driver of macrophage functions in tumors as well as the principal strategies to overcome tumor immunosuppression by targeting the NF-κB pathway.

The Immune Suppressor IGSF1 as a Potential Target for Cancer Immunotherapy.

The development of first-generation immune-checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. Although immune-checkpoint blockade therapies have shown clinical success, a substantial number of patients yet fail to benefit. Many studies are under way to discover next-generation immunotherapeutic targets. Immunoglobulin superfamily member 1 (IGSF1) is a membrane glycoprotein proposed to regulate thyroid function. Despite containing 12 immunoglobin domains, a possible role for IGSF1, in immune response, remains unknown. Here, our studies revealed that IGSF1 is predominantly expressed in tumors but not normal tissues, and increased expression is observed in PD-L1low non-small cell lung cancer (NSCLC) cells as compared with PD-L1high cells. Subsequently, we developed and characterized an IGSF1-specific human monoclonal antibody, WM-A1, that effectively promoted antitumor immunity and overcame the limitations of first-generation immune-checkpoint inhibitors, likely via a distinct mechanism of action. We further demonstrated high WM-A1 efficacy in humanized peripheral blood mononuclear cells (PBMC), and syngeneic mouse models, finding additive efficacy in combination with an anti-PD-1 (a well-characterized checkpoint inhibitor). These findings support IGSF1 as an immune target that might complement existing cancer immunotherapeutics.

Identification and characterization of immunogenic neoantigens in colorectal cancer (CRC).

161 Background: Presentation of neoantigens, short peptides derived from tumor-specific somatic mutations, by HLA molecules triggers the activation of anti-tumor immune response. Recognition of neoantigens by autologous T cells promotes sensitivity to immune checkpoint inhibitors (ICI) in mismatch repair deficient (MMRd)/microsatellite instability high (MSI-H) tumors. Neoantigen-targeted reactivity has also been reported in microsatellite stable (MSS) tumors, and neoantigens are emerging targets for tumor vaccines and adoptive cell therapy. Here, we aimed to comprehensively assess the spectrum of immunogenic neoantigens in CRC to identify new subpopulations for these therapeutic strategies. Methods: 7,053 CRC tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (720-gene panel) and RNA (whole transcriptome) were analyzed. MSI status was determined by immunohistochemistry of MMR proteins and/or NGS. Immune epitope prediction was performed on translated peptide sequences harboring detected mutations using the NetMHCpan v4.0 method in the Immune Epitope Database, with HLA genotyping performed using arcasHLA. Immune/stromal cell abundance in the tumor microenvironment (TME) was estimated from RNA expression profiles using MCP-Counter. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed signature, TIS). Results: 6,600,005 unique peptide:allele interactions were tested, of which 368,468 (5.6%) were predicted neoantigens with patient-specific HLA alleles, including 16,184 (0.25%) with high affinity. MMRd/MSI-H tumors (6.9%) had higher neoantigen load at all affinity levels compared to MSS, with 10,243 (63.3%) and 5,621 (34.7%) of the predicted high affinity neoantigens exclusively associated with MSS and MMRd/MSI-H, respectively. 32 recurrent high affinity neoantigens were identified in > 10 samples, most frequently derived from APC mutations in MSS tumors (78% of recurrent neoantigens), and from RNF43 (25%), ASXL1 (20%), and KMT2D (15%) in MMRd/MSI-H. TIS scores positively correlated with the abundance of various immune cell populations in the TME, notably cytotoxic lymphocytes (r = 0.46). Among the recurrent high affinity neoantigens, those with the highest mean TIS scores (> 90th percentile) resulted from mutation of MSH3 (K383fs, 5.1%) and KMT2D (multiple variants, 2.8%) in MMRd/MSI-H CRC, while those in MSS CRC derived from SOX9 (multiple variants, 0.2%) and APC (multiple variants, 0.7%) but were not associated with increased mean TIS scores (~55th percentile). Conclusions: This is one of the largest studies to investigate the landscape of immunogenic neoantigens in CRC. We were able to identify candidate recurrent peptides with high HLA binding affinity and an association with a positive TIS signature supporting the role of neoantigens as potential cancer immunotherapy targets.

Oral probiotics microgel plus Galunisertib reduced TGF-β blockade resistance and enhanced anti-tumor immune responses in colorectal cancer

Transforming growth factor β (TGF-β), a versatile immunosuppressive cytokine, has gained increasing attention as a potential target for cancer immunotherapy. However, current strategies are constrained by tumor heterogeneity and drug resistance. Therapeutic probiotics, such as Escherichia coli Nissle1917 (EcN), not only regulate the gut microbiota to increase beneficial bacteria with anti-tumor effects, but also modulate immune factors within the body, thereby enhancing immunity. In this study, we developed an oral microgel delivery system of EcN@(CS-SA)2 by electrostatic interaction between chitosan (CS) and sodium alginate (SA), aiming to enhance its bioavailability in the gastrointestinal tract (GIT). Notably, EcN@(CS-SA)2 microgel showed a synergistic enhancement of the anti-tumor efficacy of Galunisertib (Gal, a TGF-β inhibitor) by inducing apoptosis and immunogenic cell death (ICD) in tumor cells, as well as promoting increased infiltration of CD8+ T cells into the tumor microenvironment (TME).