Autophagy inhibition potentiates anti-cancer activity of Sunitinib in kidney cancer cells.

BACKGROUND: Renal cell carcinoma (RCC), the most common solid tumor of the kidney, accounts for approximately 3% of all malignancies and has a higher incidence in Western countries. The current frontline treatment for metastatic RCC (mRCC) relies on immune checkpoint inhibitors (ICIs), alone or in combination with tyrosine kinase inhibitors (TKIs). Although initially effective, these therapies often lose efficacy due to the emergence of drug resistance, which severely limits long-term patient survival. Among the mechanisms exploited by cancer cells to evade treatment, autophagy has emerged as a key contributor. Here, we explore the role of autophagy in driving therapeutic resistance in kidney cancer. RESULTS: We demonstrate that metastatic RCC tissues display markedly higher levels of LC3 compared to matched primary tumors, suggesting a role of autophagy in disease progression. Pharmacological inhibition of autophagy with desmethylclomipramine (DCMI), a tricyclic antidepressant, significantly impairs RCC cell proliferation, invasion, and migration while promoting apoptosis. Notably, combining DCMI with the TKI Sunitinib enhances antitumor efficacy beyond either treatment alone, through a mechanism involving the p53/p21 pathway. CONCLUSION: Our findings underscore the importance of autophagy in the progression and therapeutic resistance of renal carcinoma. Targeting autophagy, particularly in combination with TKIs, may offer a promising strategy to overcome drug resistance and improve outcomes in patients with mRCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13062-025-00671-6.