Methyl　methanesulfonate-sensitivity　protein　22-like　(MMS22L)　is　crucial　in　protecting　genome　integrity　during　DNA　replication　by　preventing　DNA　damage　and　maintaining　efficient　homologous　recombination.　However,　the　role　of　MMS22L　in　human　cancers　remains　unclear.　Here,　we　reported　the　landscape　of　MMS22L　using　multi-omics　data　and　identified　the　relationship　between　the　MMS22L　status　and　pan-cancer　prognosis.　In　addition,　the　correlation　of　MMS22L　mRNA　expression　levels　with　tumor　mutational　burden,　microsatellite　instability,　homologous　recombination　deficiency,　and　loss　of　heterozygosity　in　pan-cancer　was　also　described　in　this　study.　Furthermore,　this　study　was　the　first　to　characterize　the　relationship　between　mRNA　expression　of　MMS22L　and　immune　cell　infiltration　in　the　tumor　microenvironment　in　human　cancer.　Concurrently,　this　study　explored　the　crucial　role　of　MMS22L　in　different　immunotherapy　cohorts　through　current　immunotherapy　experiments.　Eventually,　we　investigated　the　role　of　MMS22L　in　hepatocellular　carcinoma　(HCC).　The　results　demonstrated　that　MMS22L　is　widely　expressed　in　multiple　HCC　cell　lines,　and　our　results　emphasized　that　MMS22L　was　involved　in　HCC　progression　and　affects　the　prognosis　of　patients　with　HCC　through　multiple　independent　validation　cohorts.　Collectively,　our　findings　reveal　the　essential　role　of　MMS22L　as　a　tumor-regulating　gene　in　human　cancers　while　further　emphasizing　its　feasibility　as　a　novel　molecular　marker　in　HCC.　These　findings　provide　an　essential　reference　for　the　study　of　MMS22L　in　tumors.　Copyright　©　2022　Guo,　Liu　and　Gong.