Comparative Oncology: Cross-Sectional Single-Cell Transcriptomic Profiling of the Tumor Microenvironment Across Seven Human Cancers

<b>Background/Objectives</b>: To elucidate the differential transcriptional and intercellular signaling features of tumor components across various cancers, we conducted a comparative analysis using single-cell RNA sequencing (scRNA-seq). This technology enables detailed characterization of tumor ecosystems and may explain variations in tumor behavior among distinct cancer types. <b>Methods</b>: We analyzed publicly available scRNA-seq datasets (GEO) from seven cancer types-pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), breast cancer (BC), thyroid cancer (TC), gastric cancer (GC), and colorectal cancer (CRC)-to define their unique molecular characteristics and intercellular interactions. <b>Results</b>: PDAC displayed a distinct tumor microenvironment (TME) dominated by myeloid cells (~42%), including abundant <i>CXCR1</i>/<i>CXCR2</i>-expressing tumor-associated neutrophils (TANs) that preferentially interacted with immune rather than cancer cells. The competitive receptor <i>ACKR1</i> was minimally expressed on endothelial cells, consistent with PDAC hypo-vascularity. In HCC, tumor cells lacked <i>EPCAM</i> and expressed complement and stem cell markers; cancer-associated fibroblasts (CAFs) were scarce, and stellate cells expressed the pericyte marker <i>RGS5</i>. CAFs were abundant in ESCC and BC, with <i>IGF1</i>/<i>2</i> expression, while in GC, these markers were uniquely found in plasma cells. Since BC and GC subtypes exhibit distinct TME patterns, it is necessary to perform subtype-specific analyses for these cancers. TC showed high expression of tumor-suppressor genes, including <i>HOPX</i>, in tumor cells. Differential interactions and the presence of "dominant signaling cell populations " with dominant outgoing signals may underlie the heterogeneity in tumor aggressiveness across these cancers. <b>Conclusions</b>: Comparative scRNA-seq analysis of multiple cancers reveals distinct tumor phenotypes and cell-cell communication patterns, offering insights into the molecular architecture of human solid tumors.