Here, we report Janus kinase 1 (JAK1) and β2-microglobulin (B2M) mutations and a higher number of insertions and deletions (indels) and exposure to an MMRD-associated mutational signature—Signature 20 in the Catalogue Of Somatic Mutations In Cancer—as candidate genomic determinants of de novo resistance to ICB in MMRD EC. The gene discussed is JAK1; the disease is cancer.