Immunotherapy has revolutionized
cancer treatment. Unfortunately, most
tumor types do not respond to
immunotherapy due to a lack of immune infiltration or "cold" tumor microenvironment (TME), a contributing factor in treatment failure. Activation of the p53 pathway can increase apoptosis of
cancer cells, leading to enhanced antigen presentation, and can stimulate natural killer (NK) cells through expression of stress
ligands. Therefore, modulation of the p53 pathway in
cancer cells with wild-type TP53 has the potential to enhance
tumor immunogenicity to NK cells, produce an inflammatory TME, and ultimately lead to
tumor regression. In this study, we report simultaneous targeting of the AKT/WEE1 pathways is a novel and tolerable approach to synergistically induce p53 activation to inhibit
tumor development. This approach reduced the growth of
melanoma cells and induced plasma membrane surface localization of the ER-resident
protein calreticulin, an
indicator of immunogenic cell death (ICD). Increase in ICD led to enhanced expression of stress
ligands recognized by the activating
NK-cell receptor NKG2D, promoting
tumor lysis. WEE1/AKT inhibition resulted in recruitment and activation of immune cells, including NK cells, in the TME, triggering an inflammatory cascade that transformed the "cold" TME of B16F10
melanoma into a "hot" TME that responded to anti-
programmed cell death protein 1 (anti-PD-1), resulting in complete regression of established
tumors. These results suggest that AKT/WEE1 pathway inhibition is a potential approach to broaden the utility of class-leading anti-PD-1
therapies by enhancing p53-mediated, NK cell-dependent
tumor inflammation and supports the translation of this novel approach to further improve response rates for metastatic
melanoma.