 Clear cell renal cell carcinoma, CCRCC, is the most common form of kidney cancer worldwide. It is often treated with surgical removal of the affected organ, but up to a third of patients have metastatic disease and 25% experience a recurrence within five years. Targeted therapy drugs, such as tyrosine kinase inhibitors, TKIs, and immune checkpoint inhibitors, ICIs, are used to treat advanced cases. Additionally, the tumor microenvironment, TME, is composed of both malignant and non-malignant cells, which interact and influence each other's behavior. These interactions may contribute to the development of resistance to immunotherapeutics, suggesting that understanding the interplay between these cells could lead to improved treatments. This article was authored by Francesco La Sorsa, Monica Ritigliano, Martina Mellella, and others.