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

Introduction/Rationale: Lung cancer is the deadliest pulmonary malignancy, driven in part by immune evasion and limited treatment options. Among key immunoregulatory players, tumor-associated macrophages (TAMs) promote angiogenesis, immunosuppression, and metastasis via M2-like polarization. MARCKS (myristoylated alanine-rich C-kinase substrate), an oncogenic regulator, is highly expressed in both tumor cells and TAMs, with elevated levels linked to cancer progression. However, its role in TAM-mediated immune modulation remains poorly understood.

Methods: We analyzed single-cell RNA sequencing data from lung cancer patients. TAMs were stratified into MARCKS-proficient (MARCKS⁺) and -deficient (MARCKS⁻) subsets. Differential expression and pathway enrichment analyses were performed, and CellChat was used to assess intercellular communication.

Results: MARCKS⁺ TAMs were enriched for immunosuppressive pathways, including IL-10 family cytokines, efferocytosis, and CD163-associated M2 programs. CCR5-related pathways implicated proliferative and migratory signaling, while suppression of T cell immunity suggested immune evasion. CellChat analysis showed significantly increased communication by MARCKS⁺ TAMs. Key outgoing ligands included SPP1, CCL, MIF, VEGF, TNF, and TGF-β, whereas incoming signals featured TGF-β, TNF, ITGB2, and SPP1. MARCKS⁺ TAMs uniquely received TGF-β, a potent M2 inducer, and secreted SPP1, linked to metastasis, therapy resistance, and fibroblast differentiation into cancer-associated fibroblasts. MIF–CD74–CXCR4 signaling further contributed to Treg recruitment and NK cell suppression.

Conclusion: MARCKS⁺ TAMs amplify immunosuppressive signaling that enhances macrophage polarization, immune evasion, and tumor-stromal crosstalk. By driving TGF-β- and SPP1-mediated interactions with tumor and immune compartments, MARCKS emerges as a key regulator of TAM-driven immunosuppression and a potential therapeutic target in lung cancer.