Immunosuppressive Tumor Microenvironment in Colorectal Cancer Lung Metastases: Implications for Recurrence After Metastasectomy

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Purpose: Colorectal cancer (CRC) lung metastases exhibit high recurrence rates after resection, underscoring the need for improved therapeutic strategies. This study aimed to characterize the tumor microenvironment (TME) of CRC lung metastases and identify the factors associated with recurrence. Materials and Methods: Fifteen CRC patients who underwent lung metastasectomy were enrolled. Multiplex immunohistochemistry (IHC), whole exome sequencing, transcriptome profiling, and single-cell RNA sequencing (scRNA-seq) were conducted on matched tumor, adjacent and distant normal lung tissues. Immune cell populations and gene expression profiles were analyzed and correlated with clinical recurrence outcomes. Results: Exome and transcriptome analyses revealed frequent TP53, KRAS, and APC mutations. Most tumors corresponded to consensus molecular subtypes 2 and 4, characterized by immune-depleted and fibrotic features. Tumors showed downregulation of effector T and NK cell signatures. IHC revealed reduced density and increased distance of CD8+ T cells and macrophages from the epithelial cells. scRNA-seq demonstrated increased regulatory T cells and decreased NK and effector T cells in tumor. Tumor-associated macrophages (TAMs), particularly SPP1 (osteopontin)-expressing subsets, were markedly enriched in tumor and correlated with suppressed effector T cella activity. High SPP1 expression was associated with early recurrence and poor overall survival. Patients with recurrence had higher proportion of PD-1+ CD8+ T cells in adjacent normal tissues. Conclusion: Immunosuppressive features including enrichment of SPP1+ TAMs and depletion of effector T and NK cells contribute to recurrence after CRC lung metastasectomy. Therapeutic strategies targeting both TAMs and T cells may enhance clinical outcomes in this patient population.

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