KRASG12D mutation drives oncogenic progression and creates an immunosuppressive microenvironment in cancers like pancreatic ductal adenocarcinoma and colorectal cancer. We investigate the immunomodulatory mechanisms of the KRASG12D inhibition and its synergy with natural killer (NK) cell therapies. We demonstrate that KRASG12D inhibition with MRTX1133 remodels the immune landscape by reducing myeloid-derived suppressor cell (MDSC) accumulation and facilitating infiltration and activation of NK and CD8+ T cells. Crucially, MRTX1133 reverses systemic immunosuppression, restoring the fitness of adoptively transferred NK cells. Mechanistically, KRASG12D inhibition impairs IFNGR1 palmitoylation and subsequent lysosomal degradation. MRTX1133 stabilizes IFNGR1 by reducing palmitoyltransferase expression and the palmitate pool. This stabilization increases IFN-γ/IFNGR signaling and up-regulates NK cell-activating ligands ICAM1 and ULBP1, thereby sensitizing cancer cells to NK cells. Consequently, combining MRTX1133 with IL-15 or adoptive NK cell therapy yields synergistic antitumor responses and prolonged survival. Our findings provide mechanistic rationale for combining KRASG12D inhibitors with NK cell-based immunotherapies to improve outcomes for patients with KRASG12D-mutant cancers.

Adenosine deaminase acting on RNA 1 (ADAR1) is a critical enzyme that catalyzes the conversion of adenosine to inosine in double-stranded RNA (dsRNA). By modifying endogenous dsRNA, ADAR1 prevents erroneous recognition by cytoplasmic dsRNA sensors, including MDA5, PKR, and ZBP1. Inhibition of ADAR1’s deaminase activity can activate MDA5-mediated innate immune responses and stimulate interferon production, while blocking ADAR1’s RNA-binding activity can induce PKR-mediated translational shutdown and cell death. Emerging evidence suggests that silencing ADAR1 enhances tumor responsiveness to immune checkpoint inhibitors, highlighting ADAR1 as a promising target in cancer immunotherapy. In this study, we aimed to develop small-molecule inhibitors of ADAR1 as potential therapeutic agents for ADAR1-dependent cancers. A primary RNA-editing assay was established to screen a library of 265,000 compounds, leading to the identification of 505 initial hits. These hits underwent triage validation involving target engagement studies, cell-based editing assays, and selectivity profiling. Among the validated compounds, RP04459 emerged as a lead candidate for further investigation. RP04459 effectively inhibited ADAR1’s RNA-editing activity in both biochemical and cellular assays. Treatment with RP04459 activated downstream interferon-β signaling in an MDA5-dependent manner, confirming its immunostimulatory potential. Detailed point mutation studies revealed the binding site of RP04459 on the ADAR1 protein, providing insight into its mechanism of action. The identification of RP04459 as a selective ADAR1 inhibitor underscores its potential to enhance immune-based therapies for cancers reliant on ADAR1 activity. Further preclinical evaluation of RP04459 may pave the way for novel therapeutic strategies in cancer immunotherapy Zijun Chen, Liqiang Shen, Qi Zhao, Jing Lu, Weiliang Li, Wen Jin, Xiang Ji, Mengchao Shi, Haowei Zhu, Lin Wang, Leduo Zhang, Xianqi Kong, Dawei Chen, Tianlun Zhou, Jiasheng Lu. Discovery of a small molecule inhibitor of ADAR1 for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4288.

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints. Lymphoplasmacytic lymphoma is a B-cell low-grade lymphoma with no approved standard therapy. Here the authors report a non-randomized phase 1 clinical trial performing early intervention with personalized neoantigen vaccines in asymptomatic patients and associating clinical efficacy with successful perturbation of the tumor immune microenvironment.

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade B-cell lymphoma, characterized by the presence of clonal tumor cells infiltrating the bone marrow. Despite a cumulative risk of progression, there is no approved therapy for patients in the asymptomatic phase. We conducted a first-in-human clinical trial of a novel individualized therapeutic DNA idiotype neoantigen vaccine as an early intervention in nine patients with untreated asymptomatic LPL. The vaccine platform encoded the autologous LPL-derived Ig single chain variable fragment fused to human chemokine CCL20 (macrophage inflammatory protein-3, MIP-3a), which was designed to trigger T-cell immunity by targeting delivery of the expressed fusion protein to antigen presenting cells. The vaccine was well tolerated with no dose limiting toxicities. One patient achieved a minor response, and all remaining patients experienced stable disease, with median time to disease progression of 61+ months, which compares favorably to median time to progression of 3.9 years in published series. Direct interrogation of the tumor microenvironment by single-cell transcriptome analysis revealed explanations for lack of more robust objective clinical responses. Comparing paired pre- and post- vaccine bone marrow samples, we observed a striking dichotomous pattern of significantly reduced numbers of clonal tumor cells, identified by their unique BCR sequences, and downregulation of genes involved in signaling pathways critical for B-cell survival among the mature B cells subpopulation post-vaccine in the majority of patients, but no change in clonally related plasma cell-like clusters of any patient (Figure 1). Downregulation of HLA molecule expression suggested intrinsic resistance by tumor plasma cell subpopulations and cell-cell interaction analyses predicted paradoxical upregulation of IGF signaling post vaccine by plasma cell, but not mature B-cell subpopulations, suggesting a potential mechanism of acquired resistance. Vaccine therapy induced dynamic changes in bone marrow T-cells, including upregulation of signaling pathways involved in T-cell activation, expansion of T-cell clonotypes (Figure 2), increased T-cell clonal diversity, and functional tumor idiotype-specific cytokine production, with little change in co-inhibitory pathways or Treg. Vaccine therapy also globally altered cell-cell communication networks across various bone marrow cell types. CellChat analysis inferred significant downregulation of signaling pathways post-vaccine that likely directly promote growth of LPL cells, such as APRIL and IL-6 which are known to promote B- or plasma cell survival. Other pathways were reduced post-vaccine, such as RESISTIN, which has a known role in supporting proliferation of solid cancers. A role for RESISTIN in supporting LPL has not been previously inferred, but it has been reported to induce multidrug resistance in multiple myeloma. Bioinformatic analysis also identified a predominant role for myeloid cells in the tumor microenvironment as a source of vaccine-induced, downregulated pro-tumoral signaling to LPL cells. The pathways affected were primarily associated with monocytic, rather than granulocytic or dendritic cell subpopulations, particularly non-classical CD14 -CD16 + monocytes, and to a lesser extent classical CD14 +CD16 - monocytes . Recent reports indicate that an increased pro-inflammatory myeloid signature is an early step in the development of LPL and in monoclonal gammopathy of undetermined significance. Taken together, these results suggest that this prototype neoantigen vaccine favorably perturbed the tumor immune microenvironment, resulting in reduction of clonal tumor mature B-cell, but not plasma cell subpopulations. Future functional studies of the pathways affected are needed to confirm mechanisms of resistance elucidated and to design combination strategies to circumvent them. Such strategies could include adding IFN gamma or epigenetic drugs, designed to increase HLA molecule expression on plasma cell-like LPL subpopulations and combining neoantigen vaccines with agents that specifically target plasma cells or pathways known to promote their growth, such as IGF-1 receptor inhibitors. Finally, our data suggest that combinations of these vaccines with myeloid cell checkpoint blockade may be worthwhile.

Supplementary Figure 6 from Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy

Supplementary Figure 1 from Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy

Supplementary Figures 1-4 from IL-17 Enhances Tumor Development in Carcinogen-Induced Skin Cancer

Supplementary Figure 1 from STAT3 Inhibition Is a Therapeutic Strategy for ABC-like Diffuse Large B-Cell Lymphoma

Abstract Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade B-cell lymphoma of the bone marrow. Despite a cumulative risk of progression, there is no approved therapy for patients in the asymptomatic phase. We conducted a first-in-human clinical trial of a novel therapeutic DNA idiotype neoantigen vaccine in nine patients with asymptomatic LPL. Treatment was well tolerated with no dose limiting toxicities. One patient achieved a minor response, and all remaining patients experienced stable disease, with median time to disease progression of 61+ months. Direct interrogation of the tumor microenvironment by single-cell transcriptome analysis revealed an unexpected dichotomous antitumor response, with significantly reduced numbers of clonal tumor mature B-cells, tracked by their unique BCR, and downregulation of genes involved in signaling pathways critical for B-cell survival post-vaccine, but no change in clonal plasma cell subpopulations. Downregulation of HLA class II molecule expression suggested intrinsic resistance by tumor plasma cell subpopulations and cell-cell interaction analyses predicted paradoxical upregulation of IGF signaling post vaccine by plasma cell, but not mature B-cell subpopulations, suggesting a potential mechanism of acquired resistance. Vaccine therapy induced dynamic changes in bone marrow T-cells, including upregulation of signaling pathways involved in T-cell activation, expansion of T-cell clonotypes, increased T-cell clonal diversity, and functional tumor antigen-specific cytokine production, with little change in co-inhibitory pathways or Treg. Vaccine therapy also globally altered cell-cell communication networks across various bone marrow cell types and was associated with reduction of protumoral signaling by myeloid cells, principally non-classical monocytes. These results suggest that this prototype neoantigen vaccine favorably perturbed the tumor immune microenvironment, resulting in reduction of clonal tumor mature B-cell, but not plasma cell subpopulations. Future strategies to improve clinical efficacy may require combinations of neoantigen vaccines with agents which specifically target LPL plasma cell subpopulations, or enable blockade of IGF-1 signaling or myeloid cell checkpoints.

Supplementary Figure Legends 1-3 from STAT3 Inhibition Is a Therapeutic Strategy for ABC-like Diffuse Large B-Cell Lymphoma

Supplementary Figure 2 from Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy

Supplementary Figure 2 from Targeting Stat3 in the Myeloid Compartment Drastically Improves the In vivo Antitumor Functions of Adoptively Transferred T Cells

Supplementary Figure 1 from Targeting Stat3 in the Myeloid Compartment Drastically Improves the In vivo Antitumor Functions of Adoptively Transferred T Cells

Supplementary Figure 7 from Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy

Supplementary Figure 4 from Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy

Supplementary Figure 5 from Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy

Prostate cancer (PCa) is the third most common malignancy worldwide. Novel and effective therapeutic targets are needed for PCa. The purpose of this study was to discover novel therapeutic targets for PCa by performing advanced analysis on PCa RNA sequencing (RNAseq) data from The Cancer Genome Atlas (TCGA). Weighted correlation-network analysis (WGCNA) was performed on the RNAseq data of tumor samples, and the module most relevant to the Gleason score was identified. Combining differential gene-expression analysis and survival analysis, we narrowed down potential therapeutic target genes and found that PKMYT1 might be one. Subsequently, functional studies (i.e., cell-proliferation assays, cell cycle analysis, and colony-formation assays) demonstrated that knockdown of PKMYT1 significantly inhibited the growth of PCa cells. Further investigation illustrated that PKMYT1 promoted the growth of PCa cells through targeting CCNB1 and CCNE1 expression. In addition, fostamatinib, an inhibitor of PKMYT1, effectively inhibited the proliferation of PCa cells. Taken together, our results suggest that PKMYT1 is a gene associated with malignancy of PCa and is a novel therapeutic target.

Li-Fraumeni Syndrome (LFS), which is a rare dominantly inherited cancer predisposition syndrome, is associated with germline P53 mutations. Mutations of the tumor suppressor protein P53 are associated with more than 50% of human cancers; however, almost 30% of P53 mutations occur rarely and this has raised questions about their significance. It therefore appeared of particular interest that we identified a novel mutation in a patient suffering from breast cancer and fulfilling the diagnostic criteria of LFS. In this study, a patient with remarkable family history developed breast cancer and was diagnosed with LFS. By performing next-generation sequencing on the patient and subsequent verification by Sanger sequencing among other family members, a new germ-line P53 replication error, a trinucleotide repeat mutation in the coding region, was identified in two generations of this Li-Fraumeni family.

BACKGROUND:Permanent prostate brachytherapy (PPB) is an effective treatment choice for low and intermediate risk prostate cancer (PCa). However, the impact of PPB on tumor immune status is still poorly understood. This study aimed to assess the immune status in PCa patients before and at different time points after PPB (1, 3, 6, and 12 months).METHODS:Blood was collected from 32 patients with low and intermediate risk PCa and 12 healthy volunteers. The frequency of immunocompetent cells was identified by flow cytometry. The concentration of immunoglobulins and complements was detected by ELISA.RESULTS:Various immunocompetent cells were dysregulated in PCa patients compared with healthy volunteers. Peripheral serum prostate-specific antigen (PSA) decreased rapidly at the first month after PPB treatment, and the peripheral serum PSA became very low at 6 months after PPB treatment. CD3+ T cells, CD4+ T cells, CD3-CD16+/56+ natural killer (NK) cells were increased significantly at certain time points after PPB. Although the percentage of the CD8+ T cells did not change markedly, the ratio of CD4/CD8 increased significantly at 3 months after PPB (P=0.0196). There was no influence of PPB on B cells number, but the concentration of immunoglobulins IgM, IgG, and IgA, and complements C3 and C4 in patients increased at some time points after PPB.CONCLUSION:The immunocompetent cells are dysregulated in PCa patients. PPB treatment could effectively kill tumor cells and then stimulate cellular immunity and humoral immunity in PCa patients.