TLSB-09 TARGETED P16 KNOCKOUT CONFERS AN IMMUNOSUPPRESSIVE MICROENVIRONMENT IN PRECLINICAL MODELS OF TRIPLE NEGATIVE BREAST CANCER BRAIN METASTASIS

Tumor-derived PTX3 drives an immunosuppressive myeloid landscape and inhibits CD8 T cell-mediated anti-tumor immunity via PI3K-dependent signaling.

Abstract B055: Targeting LSD1 for anti-PD1 therapy resistance mechanism in Head and Neck Cancer for future therapy

Head and Neck Squamous cell carcinoma (HNSCC) frequently exhibits resistance to anti–PD-1 immune checkpoint blockade. We asked whether dysregulated major histocompatibility complex class I (MHC-I) is a determinant of anti–PD-1 resistance, and whether targeting Lysine-specific demethylase 1 (LSD1/KDM1A) is an effective strategy. LSD1 promotes phospho-CDK7– and STAT3-mediated tumor growth and immunosuppression, whereas it promotes dendritic cells and CD8+ T cell-mediated antitumor immunity. Effects of SP2509 ± anti–PD-1 (pembrolizumab) were evaluated in (1) a humanized orthotopic NCG model bearing MHC-I–deficient HNSCC stem-cell tumors and (2) an MHC-I-sufficient 4NQO-induced HNSCC model. Immune phenotypes were assessed by flow cytometry and immunohistology. Mechanistic studies included gene expression analyses (Batf3, Cxcl9, Cxcr3), TCGA correlations between KDM1A and immune-infiltration signatures, and PBMC co-culture assays using HNSCC lines engineered for MHC-I gain- or loss-of-function. In the humanized MHC-I–deficient model, pembrolizumab did not reduce primary tongue tumor burden by gross or histopathologic assessment; instead, it decreased tumor-infiltrating human immune populations (CD45+, CD3+, CD4+, CD8+ subsets, and DCs), consistent with immune exclusion, and was associated with increased metastatic liver lesions. In contrast, in the MHC-I-sufficient 4NQO model, anti–PD-1 reduced tumor burden and increased CD45+ leukocyte infiltration, DC accumulation, and CD69+CD8+ T cells. SP2509 attenuated tumor growth in humanized HNSCC mice, improved tumor histopathology, and remodeled the tumor immune microenvironment with minimal change in total CD45+ frequency. MHC-I loss coupled with insufficient DC and CD8+ T-cell activity drives anti–PD-1 resistance and can paradoxically exacerbate tumor progression and metastasis. SP2509 increased infiltration of CD3+, CD4+, CD8+ T cells, NKT, and NK cells and enhanced activation of CD8+, NKT, and NK populations. Mechanistically, LSD1 inhibition upregulated Batf3, Cxcl9, and Cxcr3, consistent with enhanced DC-associated antigen presentation and effector lymphocyte recruitment. TCGA analysis revealed inverse correlations between KDM1A expression and immune-infiltration genes (PTPRC/CD45, CD4, CD8A/B, ITGAX/CD11c, XCR1, CXCL9, CXCR3, IFNG). In PBMC co-culture assays, SP2509 plus anti–PD-1 induced immune activation in an MHC-I–dependent manner: MHC-I overexpression rescued immune activation in MHC-I–deficient stem cells, while MHC-I knockout reduced activation in MHC-I-sufficient HSC3 cells. Overall, LSD1 inhibition attenuated tumor growth in both MHC-I-sufficient and -deficient tumors. Pre-treatment assessment of tumor MHC-I status may predict non-responder and immune-related adverse outcomes to anti–PD-1 therapy. LSD1 inhibition promotes MHC-I–dependent antigen presentation, Batf3/DC-linked signaling, and effector lymphocyte activation, providing a rational strategy to overcome MHC-I–associated resistance to anti–PD-1 therapy in HNSCC/OSCC. Amit Chakraborty, Rajnikant Raut, Chumki Choudhury, Bikash Sahay, Manish V. Bais. Targeting LSD1 for anti-PD1 therapy resistance mechanism in Head and Neck Cancer for future therapy [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B055.

IFIT1+ Tumor-Associated Macrophages Suppress Cancer Stemness and Enhance Chemosensitivity via the TNFSF10-TNFRSF10B Axis in Epithelial Ovarian Cancer.

BACKGROUND Epithelial ovarian cancer (EOC) is typically diagnosed at an advanced stage and is associated with high mortality due to metastasis and chemoresistance. Cancer stem cells (CSCs) are central to EOC progression, recurrence, and treatment resistance, with their functional behavior shaped by the tumor immune microenvironment. While M1 and M2 macrophages have been well-characterized, the role of interferon-stimulated gene-enriched subpopulations, particularly interferon-induced protein with tetratricopeptide repeats 1 tumor-associated macrophages (IFIT1+ TAMs), in regulating CSC properties in EOC remains largely unexplored. METHODS Single-cell RNA sequencing (scRNA-seq) was utilized to map the myeloid landscape and trace transcriptomic evolution in EOC. An in vitro indirect culture model utilizing unpolarized macrophage (M0)-conditioned medium (CM) was established to assess baseline phenotypic alterations. Furthermore, targeted siRNA silencing (si-TNFRSF10B) combined with recombinant human tumor necrosis factor ligand superfamily member 10 (TNFSF10) (rhTRAIL) treatments were employed to evaluate the specific impact of the TNF-related apoptosis-inducing ligand (TRAIL)-Death receptor 5 (DR5) signaling axis on multidrug resistance and CD44 expression. RESULTS High-resolution scRNA-seq analysis revealed a stage-dependent decline in IFIT1+ TAMs, an interferon-primed subset that robustly expresses the TNFSF10 ligand during early-stage disease. In vitro assays showed that conditioned medium from M0 macrophages suppresses CSC features and enhances expression of the tumor necrosis factor receptor superfamily member 10B (Death receptor 5) (TNFRSF10B/DR5) in EOC cells. Mechanistic studies confirmed that exogenous rhTRAIL treatment markedly diminished CD44+ cell populations and enhanced sensitivity to chemotherapeutic agents. Notably, these antitumor effects were largely abrogated following siRNA-mediated silencing of the DR5 receptor in EOC cell lines. CONCLUSIONS Our findings reveal that IFIT1+ tumor-associated macrophages intrinsically harbor anti-cancer stem cell potential through the TNFSF10 ligand. Activation of the TNFSF10-TNFRSF10B pathway suppresses cancer stemness and may enhance chemosensitivity. These insights shed light on the functional diversity of macrophages, highlighting that driving tumor-associated macrophages toward a sustained, interferon-primed IFIT1+ phenotype represents a promising therapeutic approach to target cancer stem cell populations in epithelial ovarian cancer.

ZBTB33/RBM15 Axis Upregulates MACC1 to Promote the Malignant Progression of Colorectal Cancer.

Clinically, these findings not only deepen the understanding of m6A-mediated posttranscriptional regulation in CRC but also identify this axis as a promising therapeutic target for overcoming ferroptosis resistance and improving patient outcomes.

p53 hotspot mutants attenuate CTL-mediated tumor cell killing through a novel ALKBH5-YTHDF3-PD-L1 pathway

FKBP52 dictates the dual role of p53 in hepatocellular carcinoma: Mutation-specific prognostic stratification and therapeutic implications

The lack of mutation-contextual therapeutic targets remains a major barrier in hepatocellular carcinoma (HCC) management. Immunohistochemical analysis of 341 human HCC specimens identified FK506-binding protein 52 (FKBP52) as a tumor grade-associated biomarker. In vitro, FKBP52 overexpression enhanced proliferation in p53-mutant liver cancer cells but suppressed it in p53-wild-type cells. Using two murine models—subcutaneous xenografts and orthotopic liver implants—genetic manipulation confirmed that FKBP52 overexpression in Huh7 accelerated tumor growth, while shRNA-mediated knockdown attenuated growth and decreased AFP/CD133 expression. Differential p53 status underpinned this disparity. In vitro EdU incorporation assays, colony formation assays and TP53-null xenografts (Hep3B cells) demonstrated that p53 knockdown abrogated the phenotype, confirming that FKBP52 promotes mutant p53-driven tumorigenesis while suppressing wild-type p53 tumors. Mechanistically, co-immunoprecipitation (Co-IP) revealed FKBP52 binds p53 via its FK2 and TPR domains independently of mutation status. This interaction recruited MDM2 into the FKBP52-p53 complex, impairing MDM2-mediated degradation and prolonging stability of both wild-type and mutant p53. Taken together, our findings establish FKBP52 as a novel p53 stabilizer with context-dependent oncogenic effects, critically determined by p53 mutational status. These results highlight the therapeutic potential of targeting the FKBP52-MDM2-p53 axis specifically in TP53-mutant HCC.