Fatty Acid Synthase Mutations Predict Favorable Immune Checkpoint Inhibitor Outcome and Response in Melanoma and Non-Small Cell Lung Cancer Patients

SIMPLE SUMMARY: A key point in immunotherapies is to determine tumor cases that are sensitive to immune checkpoint inhibitors (ICI). Effective indicators could accurately evaluate the ICI treatment efficacy. Fatty acid synthase (FASN) is frequently mutated in tumor genomes. In this work, we consolidated genomic and clinical ICI data of melanoma and non-small cell lung cancer (NSCLC) samples, noticed that FASN mutations were linked to an elevated antitumor immunity, and were predictive of an improved ICI prognosis outcome and immunotherapeutic response rate. Our work offers a possible clinical indicator for assessing cancer ICI efficacy and selecting patients to receive immunotherapies. ABSTRACT: Fatty acid synthase (FASN) acts as the central member in fatty acid synthesis and metabolism processes, which regulate oncogenic signals and tumor immunogenicity. To date, no studies have reported the connection of FASN mutations with ICI efficacy. In this study, from 631 melanoma and 109 NSCLC patients who received ICI treatments, we retrospectively curated multiomics profiles and ICI treatment data. We also explored the potential molecular biological mechanisms behind FASN alterations. In melanoma patients, FASN mutations were observed to associate with a preferable immunotherapeutic prognosis and response rate (both p < 0.01). These connections were further corroborated by the NSCLC patients (both p < 0.01). Further analyses showed that a favorable tumor immunogenicity and immune microenvironment were involved in FASN mutations. This work confirms the clinical immunotherapy implications of FASN mutation-mediated fatty acid metabolism and provides a possible indicator for immunotherapy prognosis prediction.