KRAS Mutations Reprogram RNA m6A Modifications to Drive CD73-Dependent Immune Evasion in Colorectal Cancer.

CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC

Mediator complex kinase CDK8 is identified as a driver of resistance towards KRASG12D inhibition in pancreatic ductal adenocarcinoma (PDAC), promoting stromal remodeling and immunosuppression and CDK8 inhibition in resistant tumors re-primes PDAC to anti-CTLA-4 immunotherapy efficacy.

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

KRAS mutations as architects of the tumor immune microenvironment: implications for combination therapies

Oncogenic KRAS mutations rank among the most prevalent driver alterations in human malignancies, reaching near-universal frequency (~98%) in pancreatic ductal adenocarcinoma (PDAC) and high prevalence in colorectal cancer (CRC, ~52%) and lung adenocarcinoma (LAC, ~32%). Beyond their canonical roles in promoting cell-intrinsic proliferation and survival through the MAPK/ERK and PI3K/AKT cascades, KRAS mutations actively sculpt a profoundly immunosuppressive tumor microenvironment (TME), which constitutes a major barrier to both targeted therapy and immunotherapy. Through coordinated programs encompassing inflammatory cytokine secretion, downregulation of antigen presentation machinery, tumor-associated macrophage (TAM) reprogramming, myeloid-derived suppressor cell (MDSC) expansion, and PD-L1 upregulation, KRAS-mutant tumors establish robust immune exclusion. These programs are further stratified by co-mutations in STK11 , KEAP1 , and TP53 , which define distinct immune phenotypes ranging from inflamed to profoundly immune-excluded “cold” tumors. The recent approval of covalent KRAS G12C inhibitors, sotorasib and adagrasib, has revealed that targeted KRAS blockade can remodel the TME toward an immunostimulatory state, providing a mechanistic rationale for combining KRAS-directed agents with immune checkpoint blockade, STING agonists, and neoantigen vaccines. This mini-review synthesizes the current knowledge of KRAS-immune crosstalk, highlights existing controversies and research gaps, and evaluates emerging combination strategies designed to convert immune exclusion into durable anti-tumor immunity.

METTL3–YTHDF1–driven m6A enhancement of MYC signaling orchestrates DNA repair and metabolic reprogramming to promote chemoresistance in colorectal cancer

MLL4/KMT2D mutations increase immune activity and predict therapy efficacy in colorectal cancer

Background The KMT2D histone 3-lysine 4 methyltransferase (also known as MLL4) is a critical chromatin regulator, which is frequently inactivated by gene mutations in various types of cancer including colorectal cancer (CRC). Several lines of evidence suggest a strong association between chromatin regulation, tumor immunity and drug sensitivity. To explore the role of KMT2D in tumor immunity, we analyzed genomic and clinical datasets from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center for various cancer entities. Result The results showed that KMT2D-mutated CRCs displayed a significantly higher expression of immune checkpoint regulators including PD-L1, CTLA4 and CD8 when compared to KMT2D wild-type CRCs. Mutations in KMT2D correlate with elevated T-effector and interferon-γ gene signatures indicating infiltration with active immune cells. By performing immune cell deconvolution from transcriptomic data, CRCs harboring KMT2D mutations are associated with increased infiltration of CD8+ T cells, NK cells and macrophages, but they display low amounts of Treg cells suggesting that KMT2D loss-of-function mutations correlate with an immunologically “hot tumor” phenotype. Furthermore, patients with KMT2D mutant CRC displayed better clinical responses to immune checkpoint inhibitor (ICI) therapy with an improved overall patient survival compared to patients with KMT2D wild-type CRC. Importantly, this effect did not exist in cohorts of CRC patients, which have not been treated with immunotherapies. To further understand the differential drug response effect related to KMT2D, we treated wild-type and KMT2D inactive epithelial cells with various cancer drugs. KMT2D mutant cells exhibited increased DNA damage and higher sensitivity to cisplatin in comparison to KMT2D wild-type cells. Conclusions KMT2D loss-of-function mutations are associated with a positive outcome of immunotherapy efficacy in CRC and responses to cisplatin treatments. The stratification of CRC patients by KMT2D gene status may enable personalized approaches by identifying CRC patient populations that benefit from ICI therapy and chemotherapy.

LTBP4 deficiency induces MRC1+/CD44+ macrophages to drive cancer progression in preclinical colorectal cancer models.

The tumor microenvironment is crucial for cancer progression, but the mechanisms underlying the tumor-immune cell interactions in it remain poorly understood. Here, we identified latent transforming growth factor-β (TGFβ) binding protein 4 (LTBP4) deficiency in colorectal cancer (CRC) as a critical driver that reprogrammed tumor-associated macrophages (TAMs) and induced a distinct subset, which promoted tumor progression by coordinating immune evasion and extracellular matrix (ECM) remodeling. Clinically, LTBP4 deficiency correlated with CRC progression and poor patient survival. Ltbp4 knockout markedly promoted tumor growth and metastasis in immunocompetent mice, an effect attenuated in immunodeficient hosts, establishing the essential role of host immunity in mediating the effects of LTBP4 deficiency. Single-cell RNA sequencing revealed that LTBP4 deficiency induced a mannose receptor C-type 1-positive (MRC1+)/CD44+ TAM subset and correlated with reduced CD8+ T cell infiltration. Mechanistically, LTBP4 deficiency increased active TGFβ1 levels, which acted in a paracrine manner to up-regulate MRC1 in TAMs, whereas autocrine signaling induced HAS2 (hyaluronan synthase 2) expression and hyaluronan production to increase CD44. CD44 signaling in TAMs up-regulated matrix metalloproteinases for collagen degradation, whereas MRC1 mediated collagen internalization, cooperatively remodeling the ECM to facilitate tumor invasion. The TGFβ1-driven MRC1+/CD44+ TAMs further suppressed CD8+ T cell function by diminishing the C-X-C motif chemokine ligand 16-C-X-C motif chemokine receptor 6 (CXCL16-CXCR6) axis. Therapeutically, targeted depleting MRC1+/CD44+ TAMs enhanced the efficacy of PD-1 (programmed cell death-1) blockade in LTBP4-deficient tumors. Our study positions LTBP4 as a key modulator of tumor progression and reveals a therapeutic strategy for LTBP4-deficient CRC.