Immune-intrinsic MLKL regulates dendritic cell maturation and CD8+ T cell effector function in anti-tumor immunity
4 affiliations
- 1Graduate Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- 2Department of Pathology and Krantz Family Center for Cancer Research, Mass General Brigham Cancer Center and Harvard Medical School, Boston, MA USA
- 3Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- 4Center of Excellence for Cancer and Inflammation, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
Abstract
Background: Anti-tumor immunity relies on coordinated interactions between dendritic cells (DCs) and cytotoxic CD8⁺ T cells to eliminate malignant cells. Mixed lineage kinase domain-like protein (MLKL), a key executioner of necroptosis, has recently been implicated in cancer through necroptosis-independent functions and is being explored as a therapeutic target. However, most studies have focused on tumor cells, whereas the immune-intrinsic functions of MLKL remain poorly understood. In particular, MLKL expression across immune cell subsets and its role in anti-tumor immunity have not been systematically investigated.
Results: Transcriptomic analyses revealed broad MLKL expression across multiple immune cell subsets, including neutrophils, monocytes, dendritic cells, and activated/memory Tcell subsets. Consistent with these findings, MLKL was upregulated in primary mouse immune cells following activation, including Tcell stimulation, bone marrow-derived dendritic cell (BMDC) maturation, and M1 macrophages. Pharmacological inhibition of MLKL impaired BMDC maturation, reduced DC-mediated CD8⁺ T cell priming, and suppressed CD8⁺ T cell activation, proliferation, and cytotoxic killing of B16-OVA tumor cells. Integrated single-cell RNA sequencing analyses from cancer patients receiving immune checkpoint blockade (ICB) further showed that MLKL expression was enriched in activated and effector CD8⁺ T cell subsets. Donor-level analyses showed higher MLKL expression in T cells from ICB responders than in those from non-responders, particularly in post-treatment samples. These findings associate MLKL expression with activated and effector anti-tumor Tcell states and suggest its potential relevance to ICB response.
Conclusions: Collectively, these findings show that MLKL is upregulated during immune activation and contributes to DC maturation and CD8⁺ T cell effector responses. Our findings highlight the context-dependent roles of MLKL across tumor and immune compartments and emphasize the importance of considering immune-intrinsic MLKL functions in the development of MLKL-targeted therapies for precision cancer immunotherapy.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13062-026-00931-z.
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BibTeX
@article{duangthim2026immuneintrinsic,
title = {{Immune-intrinsic MLKL regulates dendritic cell maturation and CD8+ T cell effector function in anti-tumor immunity}},
author = {Nattaya Duangthim and Thanpisit Lomphithak and Shumeng Hao and Francesca S. Gazzaniga and Siriporn Jitkaew},
journal = {Biology Direct},
year = {2026},
month = aug,
doi = {10.1186/s13062-026-00931-z},
url = {https://doi.org/10.1186/s13062-026-00931-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Immune-intrinsic MLKL regulates dendritic cell maturation and CD8+ T cell effector function in anti-tumor immunity
AU - Nattaya Duangthim
AU - Thanpisit Lomphithak
AU - Shumeng Hao
AU - Francesca S. Gazzaniga
AU - Siriporn Jitkaew
PY - 2026
DA - 2026/08/06
JO - Biology Direct
DO - 10.1186/s13062-026-00931-z
UR - https://doi.org/10.1186/s13062-026-00931-z
AB - Background: Anti-tumor immunity relies on coordinated interactions between dendritic cells (DCs) and cytotoxic CD8⁺ T cells to eliminate malignant cells. Mixed lineage kinase domain-like protein (MLKL), a key executioner of necroptosis, has recently been implicated in cancer through necroptosis-independent functions and is being explored as a therapeutic target. However, most studies have focused on tumor cells, whereas the immune-intrinsic functions of MLKL remain poorly understood. In particular, MLKL expression across immune cell subsets and its role in anti-tumor immunity have not been systematically investigated. Results: Transcriptomic analyses revealed broad MLKL expression across multiple immune cell subsets, including neutrophils, monocytes, dendritic cells, and activated/memory Tcell subsets. Consistent with these findings, MLKL was upregulated in primary mouse immune cells following activation, including Tcell stimulation, bone marrow-derived dendritic cell (BMDC) maturation, and M1 macrophages. Pharmacological inhibition of MLKL impaired BMDC maturation, reduced DC-mediated CD8⁺ T cell priming, and suppressed CD8⁺ T cell activation, proliferation, and cytotoxic killing of B16-OVA tumor cells. Integrated single-cell RNA sequencing analyses from cancer patients receiving immune checkpoint blockade (ICB) further showed that MLKL expression was enriched in activated and effector CD8⁺ T cell subsets. Donor-level analyses showed higher MLKL expression in T cells from ICB responders than in those from non-responders, particularly in post-treatment samples. These findings associate MLKL expression with activated and effector anti-tumor Tcell states and suggest its potential relevance to ICB response. Conclusions: Collectively, these findings show that MLKL is upregulated during immune activation and contributes to DC maturation and CD8⁺ T cell effector responses. Our findings highlight the context-dependent roles of MLKL across tumor and immune compartments and emphasize the importance of considering immune-intrinsic MLKL functions in the development of MLKL-targeted therapies for precision cancer immunotherapy. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13062-026-00931-z.
SN - 1745-6150
ER -