Related Experiment Video
Updated: Sep 26, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Targeting WEE1/AKT Restores p53-Dependent Natural Killer-Cell Activation to Induce Immune Checkpoint Blockade
Saketh S Dinavahi1, Yu-Chi Chen1, Kishore Punnath1
1Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
Abstract:
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.
Insights
Targeting AKT/WEE1 pathways synergistically activates p53, turning "cold" tumors "hot" and enhancing immunotherapy response. This novel approach promotes natural killer cell activity and tumor regression in melanoma.
Area of Science:
- Oncology
- Immunology
- Cancer Therapeutics
Background:
- Most tumors are unresponsive to immunotherapy due to a
- cold
- tumor microenvironment (TME) lacking immune infiltration.
- p53 pathway activation can enhance cancer cell apoptosis, antigen presentation, and natural killer (NK) cell stimulation via stress ligands.
- Modulating p53 in wild-type TP53 tumors may increase immunogenicity, create an inflammatory TME, and promote tumor regression.
Purpose of the Study:
- To investigate simultaneous targeting of AKT/WEE1 pathways as a novel approach to induce p53 activation.
- To evaluate the efficacy of AKT/WEE1 inhibition in enhancing tumor immunogenicity and response to immunotherapy.
Main Methods:
- Simultaneous inhibition of AKT and WEE1 pathways in melanoma cells.
- Assessment of p53 activation, immunogenic cell death (ICD) markers (e.g., calreticulin), and NK cell-activating ligand expression.
- Evaluation of immune cell infiltration, TME modulation (from
- cold
- to
- hot
- ), and response to anti-PD-1 therapy in a B16F10 melanoma model.
Main Results:
- Combined AKT/WEE1 inhibition synergistically activated p53, reduced melanoma cell growth, and induced ICD.
- ICD increased calreticulin surface expression and stress ligand presentation, promoting NK cell-mediated tumor lysis.
- AKT/WEE1 inhibition converted the
- cold
- TME to a
- hot
- TME, recruiting and activating immune cells, including NK cells.
- This approach sensitized tumors to anti-PD-1 therapy, leading to complete regression of established B16F10 melanoma.
Conclusions:
- Simultaneous AKT/WEE1 pathway inhibition is a tolerable and effective strategy for synergistic p53 activation.
- This approach enhances tumor immunogenicity through p53-mediated, NK cell-dependent inflammation.
- AKT/WEE1 inhibition holds promise for improving response rates to anti-PD-1 therapies in metastatic melanoma by overcoming TME-related resistance.
Related Concept Videos
01:27Tumor Immunotherapy
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:31The Intrinsic Apoptotic Pathway
02:23Abnormal Proliferation