Abstract
Amino acid metabolism plays a crucial role in cancer progression and invasion by modulating immune responses within the tumor microenvironment and tumor immune response. Transmembrane transport of cellular amino acids is mediated by members of the cationic amino acid transporters SLC7 family, a group of cationic amino acid transporters. Dysregulation of SLC7 family genes can disrupt systemic homeostasis, contributing to a variety of diseases, including multiple cancer types. Additionally, SLC7 family members can alter amino acid metabolic plasticity, further influencing tumor adaptation and progression. However, the precise impact of SLC7 family genes within the cancer microenvironment remains largely unexplored. This study analyzed the expression patterns, genomic alterations (single nucleotide variants, copy number variations, methylation levels), pathway activations, and clinical and subtype associations of SLC7 family genes across The Cancer Genome Atlas (TCGA) pan-cancer cohort. SLC7 activity was quantified using the ssGSEA function of the “GSVA” package to generate the SLC7 score, which was found to correlate with oncogenic and immune-related pathways, including mTORC1 signaling, interferon-gamma response, and inflammatory pathways. In vitro validation was conducted using multiple cancer cell lines (A549, H1299, HCT116, FaDu, Panc-1) and counterparts (BxPC-3, SW480, H460, BEAS-2B, FHC, HaCaT). Gene knockdown was achieved by siRNA transfection, followed by quantitative PCR, Western blotting, and functional assays assessing proliferation, invasion, and ferroptosis (iron and GSH levels) under erastin treatment. SLC7 family genes showed significant associations with immune infiltration and poor prognosis across various cancers. The SLC7 score demonstrated strong positive correlations with malignant and immune-related pathways, such as mTORC1 signaling, interferon-gamma response, and inflammatory response across the pan-cancer cohort. Elevated SLC7 scores were also associated with enhanced immune-related characteristics, and SLC7 genes, particularly SLC7A8 and SLC7A9, emerged as promising predictive markers for response to immune checkpoint inhibitor therapy (Atezolizumab) in cancer patients. Among SLC7 family genes, SLC7A5 expression was markedly elevated in KRAS-mutant tumor cell lines and was required for KRAS-driven proliferation and invasion. SLC7A11 was highly expressed in multiple tumor types and protected cancer cells from ferroptosis by maintaining intracellular cystine uptake and redox homeostasis. Individuals exhibiting elevated SLC7 scores and aberrant expression of SLC7 family genes demonstrate significant immune-inflammatory tumor immune microenvironment (TIME) characteristics and predictive potential for immunotherapy. Thus, the SLC7 family genes have the potential to serve as valuable biomarkers and therapeutic targets for cancer patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-34723-8.