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Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU) based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. It is essential to develop new treatment strategies in metastatic CRC patients with microsatellite stable disease, in whom immune checkpoint blockade is ineffective. Our preclinical studies showed riluzole, an oral medicine for amyotrophic lateral sclerosis, can increase intratumoral CD8⁺ T cells and suppress tumor growth in a syngeneic colon cancer mouse model. Riluzole-mediated tumor growth inhibition depends on the presence of CD8⁺ T cells and activation of cGAS/STING/IFNβ signaling. Methods: This was a single-arm phase I trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC. The dose of …