Current standards of care for metastatic clear cell renal cell carcinoma (ccRCC) include immune checkpoint inhibitors (ICIs), VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs), or the combination of both. Recently, the HIF-2alpha inhibitor belzutifan was approved for 2L+ metastatic ccRCC patients and its combination with ICIs or VEGFR-TKIs is being studied in clinical trials. Despite the initial efficacy of these SOCs, most patients eventually relapse. Relapse after VEGFR-TKIs can be due to diverse mechanisms such as activation of non-VEGF angiogenic pathways, stromal remodeling, apoptosis evasion, and HIF upregulation. Therefore, novel therapeutic approaches are needed. HiberCell has developed HC-7366, a GCN2 activator that initiates the integrated stress response, leading to translation inhibition, cell-cycle arrest, HIF-1alpha suppression, and apoptosis in cancer cells. Based on these effects, we explored the potential of HC-7366 to overcome resistance to VEGFR-TKIs in RCC models. In the 786-O ccRCC xenograft model, HC-7366 treatment at multiple doses corresponding to exposures below the MTD in humans yielded robust combination efficacy with either cabozantinib or lenvatinib. HC-7366 alone achieved 63% tumor growth inhibition (TGI), whereas cabozantinib alone induced 30% regression (1/8 PR) and lenvatinib alone produced 95% TGI. When combined, HC-7366 significantly enhanced responses, achieving 71% regression with cabozantinib and 44% regression with lenvatinib (7/8 and 2/8 PRs, respectively). The combination of belzutifan and VEGFR-TKI was inferior to the HC-7366/VEGFR-TKI doublet, with only 36% regression (1 PR) for lenvatinib/belzutifan and 53% regression (5/8 PRs) for cabozantinib/belzutifan. The triplet combination using HC-7366/belzutifan/VEGFR-TKI was more beneficial than any doublet, further improving TGI and responses. Furthermore, in a single mouse trial of 10 RCC PDX models, addition of HC-7366 to axitinib improved outcomes in 8/10 PDX models and was superior to the belzutifan/axitinib doublet in multiple models. Analysis of xenografts showed the combination of HC-7366 and lenvatinib reduced HIF signaling and broadly suppressed cell cycle, growth factor, and angiogenic signaling while simultaneously inducing pro-apoptotic pathways. Our data reveal that combination of HC-7366 with any VEGFR-TKI may be an effective treatment strategy for RCC patients and has the potential to be superior to a VEGFR-TKI/HIF-2 inhibitor combination. A phase 1b clinical trial is now ongoing to evaluate the safety, tolerability, and efficacy of both HC-7366/belzutifan and HC-7366/cabozantinib doublets in metastatic ccRCC (NCT06234605). These results will form a foundation for future evaluation of triplet combinations that integrate HC-7366, VEGFR-TKIs, and HIF-2 inhibitors.