Tumor-associated macrophages (TAMs) play an important role in the recurrence and progression of clear cell renal cell carcinoma (ccRCC). However, the specified mechanism has not been elucidated.Single-cell and transcriptome analysis were applied to characterize the heterogeneity of TAMs. SCENIC would infer regulators of different subsets of TAMs. The CellChat algorithm was used to infer macrophage-tumor interaction networks, whereas pseudo-time traces were used to parse cell evolution and dynamics.In this study, single-cell transcriptomic data of ccRCC were analyzed. Notably, the macrophages were clustered to select the cluster with a tendency toward M2-type TAM, which has an impact on the occurrence and metastasis of ccRCC. This macrophage cluster was defined as "TAM2". And this study revealed that TCF7L2 as a potential transcription factor regulating TAM2 transcriptional heterogeneity and differentiation. Pseudotime traces showed TCF7L2 trajectories during TAM2 cell cluster development. In addition, the results of cell interaction showed that TAM2 had the highest number and strength of interactions with cancer cells and endothelial cells. In vitro experiments, this study found that TCF7L2 was highly expressed in TAMs and promoted the polarization of macrophages to M2-type macrophages. And then overexpression of TCF7L2 in macrophages markedly promoted ccRCC invasion and proliferation.TCF7L2 could play a key role in the progression of ccRCC via enhancing TAMs recruitment and M2-type polarization.Copyright © 2024. Published by Elsevier Inc.