MARCKS Drives Immunosuppressive Signaling in Tumor-Associated Macrophages to Promote Lung Cancer Progression 2258297

Tumor-Associated Macrophages in the Chemoresistant Microenvironment of Gastric Cancer: Key Mechanisms and Intercellular Crosstalk.

Gastric cancer (GC) remains a leading cause of cancer-related mortality, with chemoresistance posing a critical barrier to effective treatment. Tumor-associated macrophages (TAMs), particularly the immunosuppressive M2-polarized subset, are emerging as pivotal mediators of chemoresistance within the tumor microenvironment (TME). TAMs promote resistance through multifaceted mechanisms, including activation of pro-survival signaling pathways, induction of epithelial-mesenchymal transition (EMT), and enhancement of angiogenesis. For instance, M2-like TAMs secrete CXCL5, which activates the PI3K/AKT/mTOR axis in GC cells, thereby conferring resistance to 5-fluorouracil (5-FU). Similarly, TMEM, a transmembrane protein overexpressed in cisplatin-resistant GC, drives M2 polarization of TAMs via the Wnt/β-catenin pathway, further amplifying drug resistance and tumor progression. Clinical studies reveal that high TAM infiltration correlates with poor chemotherapy response and reduced survival in GC patients. This review synthesizes current evidence on TAM-driven chemoresistance in GC, highlighting the molecular interplay between TAMs, tumor cells, and stromal components. It underscores the potential of TAM-centric therapies-including checkpoint inhibitors, epigenetic modulators, and combination regimens-to overcome resistance and improve clinical outcomes. By integrating preclinical insights and clinical data, this work provides a roadmap for developing precision therapies that exploit TAM biology to enhance chemosensitivity in GC.

Myeloid Lectin Profiling Identifies SYK as a Targetable Signaling Node for Remodeling Immunosuppressive Tumor-Associated Macrophages in Breast Cancer

Immunosuppressive tumor microenvironments (TMEs) are common in breast cancer (BC), where tumor-promoting myeloid-driven inflammation contributes to immune dysfunction and poor immunotherapy response. Lectins expressed by tumor-associated macrophages (TAMs) act as glycan-sensing immunoregulatory receptors driving immunosuppression, but whether specific myeloid lectins define immunosuppressive TAM states, or their signaling is pharmacologically targetable remain unclear. We used an orthogonal prioritization approach combining immunosuppressive stratification of the SCAN-B cohort (3207 patients), differential expression, single-cell myeloid localization, and immune-related upstream-regulator inference. Immunosuppressive tumors were enriched for Basal-like and HER2-enriched subtypes, with worse survival. This identified a 12-lectin panel, which was probed in a human 3D immunosuppressive TME model combining BC spheroids, fibroblasts, and blood-derived macrophages under agitation. Flow cytometry confirmed high expression of eight lectins, with four upregulated in TAMs. Survival analyses associated CLEC4E/Mincle, CLEC6A/Dectin-2, and CD209/DC-SIGN with poorer outcomes. As CLEC4E and CLEC6A converge on FcRγ/SYK signaling, this shared node was selected for pathway-level pharmacological perturbation. R406 reduced SYK phosphorylation and induced transcriptional remodeling in TAMs, with attenuation of immunosuppressive macrophage features, reduced CD204/CD206, increased HLA-DR, and remodeling of the soluble-factor profile. These findings define a myeloid lectin framework associated with BC immunosuppression and identify SYK as a candidate targetable node for remodeling TAMs.

Macrophage NPM1 drives anti-tumor immunity via the STAT3-CCRL2 axis

Background Although nucleophosmin (NPM1) is a well-characterized oncogene in acute myeloid leukemia, much less is known about its role in solid tumor immunity. Here, we examined the function of NPM1 in regulating anti-tumor immunity within the tumor microenvironment. Methods The proportion and functional changes of macrophages and T cells were detected by flow cytometry, the downstream regulatory genes of NPM1 were detected by RNA-seq, the binding ability of NPM1 and STAT3 was analyzed by Chip and luciferase assay. Results NPM1 inhibition or genetic deficiency promoted tumor growth in MC38 colon cancer and LLC lung cancer mice models. Npm1+/- mice exhibited enhanced infiltration and polarization of immunosuppressive M2-like tumor-associated macrophages (TAMs) and impaired CD8+ T cell function. Mechanistically, NPM1 bound to p-TAT3/STAT3 and promoted transcription of CCRL2, a key regulator of macrophage polarization. Overexpression of Npm1 in mice suppressed tumor growth, reduced M2 TAMs polarization, and enhanced CD8+ T cell-mediated anti-tumor immunity. Conclusion Our findings revealed that NPM1 protects against tumor progression by regulating TAMs polarization and T cell function via the STAT3-CCRL2 axis.

WNK4 restrains endometrial cancer progression by reprogramming macrophage polarization toward an M1-like phenotype

Targeting GEM Reprograms Macrophages and Overcomes Immunotherapy Resistance in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) exhibits heterogeneous responses to immune checkpoint blockade, highlighting the need to define tumor-intrinsic mechanisms driving resistance to PD-L1 inhibition. Here, we identified GTP-binding protein overexpressed in skeletal muscle (GEM) as a tumor cell-intrinsic regulator associated with poor response to anti-PD-L1 therapy in ESCC. GEM expression in tumor cells drove tumor-associated macrophage (TAM)-mediated immunosuppression, leading to reduced CD8⁺ T cell infiltration and impaired cytotoxic function. Mechanistically, GEM induced SERPINE1 expression that was secreted and acted on macrophage LRP1 to drive alternative activation and suppress antitumor immunity. GEM enhanced SERPINE1 expression through a MKK3-RACK1-p38-MEF2A cascade. GEM signaling was reinforced by a metabolically coupled feedback mechanism. Macrophages exposed to GEM-high tumor cells promoted tumor cell glycolysis and lactate production, which drove AARS1-dependent lactylation of GEM and strengthened its interaction with RACK1 to amplify downstream signaling. Disruption of the SERPINE1-LRP1 axis restored CD8⁺ T cell activity and enhanced response to PD-L1 blockade in vivo. Pharmacological perturbation of GEM-dependent signaling remodeled the tumor immune microenvironment and improved responses to PD-L1 blockade. Together, these findings define a GEM-SERPINE1-LRP1 signaling axis that drives macrophage-mediated immune suppression and suggest that targeting this pathway may enhance the efficacy of PD-L1 blockade in ESCC.

Macrophage PABPC4‐SPP1 Axis Orchestrates Immunosuppression in Colorectal Cancer

ABSTRACT Poly(A)‐binding proteins (PABPs) are frequently dysregulated in cancers, yet their functional roles remain largely elusive. Here, we identify that PABPC4, a member of PABPs, is upregulated during colorectal cancer (CRC) progression and associated with poor prognosis. Single‐cell transcriptomics reveals that PABPC4 is predominantly expressed in the macrophages of the tumor microenvironment (TME). Conditional knockout of Pabpc4 in macrophages (C4cKO) profoundly inhibited the progression of multiple cancers, including CRC, melanoma, and ovarian cancer. Mechanistically, C4cKO obviously enhances the local and systemic antitumor immunity, characterized by increased M1‐like macrophages and cytotoxic CD8+ T cells, and reduced M2‐like macrophages and myeloid‐derived suppressor cells. Clearance of macrophages or CD8+ T cells could abolish C4cKO‐stimulated antitumor immunity. We further demonstrate that PABPC4 stabilizes SPP1 mRNA via direct 3′UTR binding, and SPP1 restoration substantially reversed the enhanced antitumor immunity and tumor suppression in C4cKO mice. Clinically, elevated macrophage PABPC4‐SPP1 axis activity in human CRC tissues correlates with immunosuppressive phenotypes, potential immunotherapy resistance, and poor survival of patients. Collectively, our results reveal a previously undiscovered PABPC4‐SPP1 axis in macrophages, which induces tumor‐promoting macrophages and CD8+ T cell dysfunction, thereby facilitating tumor progression. Targeting the PABPC4‐SPP1 axis represents a promising strategy for cancer therapy.