Zhu, Lingling

Our research uncovers a role for ATR in responding to ECM stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2, which promotes β-catenin nuclear translocation and EMT. ATM-mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103 + dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal-to-epithelial transition to enhance antitumor immunity and mitigate metastases. Consistently, circulating HLA-DR + dendritic cells were also enhanced following treatment with the ATR inhibitor berzosertib in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR-targeted therapy may be optimized by considering both DNA damage–dependent and EMT-inducing effects of ATR ATR promotes metastasis and immunosuppression through EMT process

Peritoneal metastasis (PM) is a common and lethal complication of gastric cancer (GC), occurring in approximately 50% of patients with advanced disease. It is characterized by a highly immunosuppressive microenvironment and limited response to current systemic therapies, resulting in a median survival of only 3–6 months. The objective of this review was to explore the critical role of resident macrophages within the peritoneal immune microenvironment in the development and progression of GC PM and to discuss their potential as therapeutic targets. Peritoneal resident macrophages (PRMs), particularly the GATA6⁺ large peritoneal macrophages (LPMs), are hijacked by GC cells through metabolic reprogramming, transcriptional regulation, and paracrine signaling. These macrophages adopt a protumor M2-like phenotype, promote immunosuppression through T-cell exclusion and Treg recruitment, facilitate cancer cell adhesion and spheroid formation, and contribute to chemotherapy resistance. Emerging therapeutic strategies, including cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), nanoparticle-mediated macrophage repolarization, CSF-1 R/CCR2 axis inhibition, and chimeric antigen receptor macrophages (CAR-M), show promise in targeting these cells to restore antitumor immunity. In conclusion, resident macrophages are pivotal in shaping the immunosuppressive landscape of GC PM. Targeting these cells represents a promising avenue for novel combination therapies aimed at improving outcomes for patients with GC PM.