Methods and compositions are provided for preventing the loss of cell surface adhesion molecules and thus prevent or delay acquisition of a ADCC resistance phenotype mediated by lower expression of several cell surface molecules that contribute to cell:cell interactions and immune synapse formation including tumor target antigens, MHC Class I/II molecules and cell adhesion proteins. In certain embodiments, the method and composition blocks STAT1 and/or p-STAT1. In another embodiment, the method and composition blocks HATp300 and/or PCAF. In another embodiment the method and composition blocks S100a9/a8. In yet other embodiments, cocktails of combinations of inhibitors of two or more of p-STAT1, S100a8/a9, HAT p300, and PCAF are employed to reduce, reverse or inhibit development of ADCC resistant phenotypes.
