Targeting MDM2 in malignancies is a promising strategy for overcoming resistance to anticancer immunotherapy

Abstract

MDM2 has been established as a biomarker indicating poor prognosis for individuals undergoing immune checkpoint inhibitor (ICI) treatment for different malignancies by various pancancer studies. Specifically, patients who have MDM2 amplification are vulnerable to the development of hyperprogressive disease (HPD) following anticancer immunotherapy, resulting in marked deleterious effects on survival rates. The mechanism of MDM2 involves its role as an oncogene during the development of malignancy, and MDM2 can promote both metastasis and tumor cell proliferation, which indirectly leads to disease progression. Moreover, MDM2 is vitally involved in modifying the tumor immune microenvironment (TIME) as well as in influencing immune cells, eventually facilitating immune evasion and tolerance. Encouragingly, various MDM2 inhibitors have exhibited efficacy in relieving the TIME suppression caused by MDM2. These results demonstrate the prospects for breakthroughs in combination therapy using MDM2 inhibitors and anticancer immunotherapy.

Keywords: Anticancer immunotherapy; MDM2; Malignancies; Tumor immune microenvironment.

Fig. 1

The oncogenic function of MDM2. MDM2 facilitates the degradation of P53, consequently regulating apoptosis inhibition, EMT acceleration, and angiogenesis stimulation in various malignancies

Fig. 2

MDM2 can induce the immune tolerance of malignancies. Prolonged exposure to tumor MDM2 (referred to as MDM2-t) results in a decrease in the levels of effector T cells that specifically target MDM2-t. Effector T cells targeting MDM2-t, which remain present in peripheral blood, do not exhibit any response to additional MDM2-t restimulation. Furthermore, effector T cells targeting MDM2 that are generated by normal tissue (MDM2-n) do not possess cytotoxic properties toward tumor cells. All of these complex mechanisms contribute to the immune tolerance exhibited toward tumor cells expressing MDM2. The administration of various MDM2 inhibitors can modulate this immune tolerance, which in turn can influence the efficacy of anticancer immunotherapy

Fig. 3

MDM2 can induce the immune evasion of tumor cells. In tumor cells, MDM2 is known to increase the degradation of P53, which consequently results in a decline in the levels of natural killer cell-activating receptors (NK-ARs) and NK-mediated killing. Additionally, MDM2 in these cells can directly impede CD4 + T cells, as well as the production of interleukin-2 (IL-2) and interferon-γ (IFN-γ). Furthermore, MDM2 in CD4 + T cells hinders NFATc2 expression, thereby suppressing the activation of these cells. However, MDM2 in CD8 + T cells can actually stabilize STAT5 and boost their activation. Despite this, APG-115 presents an effective opportunity to upregulate both P53 and MDM2 and thereby enhance the anticancer immunity induced by CD8 + T cells. The figure also demonstrates the effectiveness of MDM2 inhibitors in inhibiting immune evasion induced by MDM2