SMAD4 and pachyonychia congenita: In contrast to the aforementioned enhanced OXPHOS in M2 macrophages, EVs derived from pancreatic cancer (PC) cells with SMAD4 deletion (a mutation that exists in 55% of tumors and carries a worse prognosis), create an immunosuppressive myeloid cell background by increasing calcium fluxes and glycolysis through the transfer of SMAD4-related, differentially expressed miRNAs and proteins [72].