Spatio-temporal heterogeneity in cancer evolution and tumor microenvironment of renal cell carcinoma with tumor thrombus

Metastasis is the most fatal aspect of cancer, often preceded by a tumor thrombus (TT) which forms within the vascular system. Renal cell carcinoma (RCC), the predominant form of kidney cancer, witnesses a venous system invasion in 4–10% of cases, resulting in venous tumor thrombus (RCC-TT). This variant represents a formidable clinical challenge due to its escalated surgical complexity, heightened risk of progression and metastasis, and an adverse prognosis. However, recent trials addressing RCC-TT face significant barriers stemming from the profound inter- and intra-tumoral heterogeneity, patient-specific treatment variations, and distinct therapeutic resistance patterns between the primary tumor (PT) and the TT. This review delves into the unique evolutionary pathway of RCC-TT, the relationship between the staging and grading of RCC-TT invasion patterns, and the spatial molecular profiling of RCC-TT. Additionally, we assess the temporal heterogeneity among TT, PT, and distant metastases, as well as the functional phenotypes of TME components. An outlook for future research on RCC-TT is also provided.