About

Michael B. Yaffe is the David H. Koch Professor in Science and Biological Engineering at MIT, where he also serves as the Director of the MIT Center for Precision Cancer Medicine and is an intramural faculty member at the Koch Institute. His research focuses on understanding how signaling pathways are integrated at the molecular and systems levels to control cellular responses. His main areas of investigation include signaling pathways and networks that regulate cell cycle progression and DNA damage responses in cancer and cancer therapy, as well as the cross-talk between inflammation, cytokine signaling, and cancer. Much of his work emphasizes how modular protein domains and kinases collaborate to build molecular signaling circuits, with the goal of applying this knowledge to design synergistic drug combinations for personalized treatment of human diseases.

Research topics

• Biology
• Biochemistry
• Computational biology
• Cell biology
• Chemistry

Selected publications

• MAPKAP Kinase 2 Orchestrates Memory T Cell Inflation in Cytomegalovirus Infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-20

  articleOpen access

  Abstract Memory T cell inflation is a distinctive immunological phenomenon observed during persistent viral infections, such as Cytomegalovirus (CMV). Unlike conventional memory T cell responses, which contract after infection resolution, a subset of CMV-specific T cells undergoes a progressive and sustained expansion, termed “inflation”, which is thought to be critical for long-term immune surveillance. The molecular mechanisms that govern memory T cell inflation remain incompletely understood, yet they are pivotal for understanding immune persistence and designing strategies against chronic viral infections. In this study, we investigate the role of MAP kinase-activated protein kinase 2 (MK2), a key downstream effector of p38 MAPK signaling, in regulating T cell responses during murine CMV (MCMV) infection. Using MK2 knockout (MK2-KO) mice, we demonstrate that MK2 deficiency alters the dynamics of MCMV-specific CD8⁺ T cell responses without impairing viral control or tissue replication. MK2 deficiency led to a reduction in non-inflationary MCMV-specific CD8⁺ T cells during the acute phase, followed by enhanced expansion of inflationary CD8⁺ T cell subsets during persistence. Furthermore, MK2-KO mice exhibited impaired effector differentiation, as evidenced by decreased expression of the terminal differentiation marker KLRG1 on MCMV-specific CD8⁺ T cells. Collectively, these findings identify MK2 as a pivotal regulator of CD8⁺ T cell magnitude, kinetics, and phenotype during both acute and chronic MCMV infection. By elucidating the role of MK2 in the regulation of memory T cell inflation, this study provides new mechanistic insight into immune regulation with implications for vaccination, chronic infection, and immune aging. Graphical abstract The graphical abstract was created using BioRender ( https://biorender.com/ ).

  PublisherDOI

• Abstract 1331: The Kinase Library: A global atlas of the human protein kinome and its applications in cancer.

  Cancer Research · 2026-04-03

  article

  Abstract Mass-spectrometry-based phosphoproteomics now profiles phosphorylation at proteome scale, yet converting site-level measurements into coherent, kinase-centered biology remains a persistent barrier to interpretation and action. The Kinase Library addresses this gap with the first-in-class, unbiased, experimentally characterized motif atlas of the human kinome, coupled to enrichment frameworks that translate phosphoproteomics data into quantitative maps of kinase activity. Rather than relying on heterogeneous annotations or heuristic rules, KL grounds inference in experimentally derived kinase-substrate relationships, providing a principled basis for comparative signaling analysis. The Kinase Library has broad utility across discovery and translational applications. It enables mechanism-of-action profiling for small molecules and combinations; delineates adaptive signaling and resistance trajectories; supports time-course and dose-response studies to resolve pathway dynamics; and stratifies models and patients in low-N-high-D (few samples with high dimensionality of data) settings where conventional statistics underperform. In clinical and preclinical contexts alike — cell lines, organoids, xenografts, and patient specimens — the Kinase Library delivers harmonized, interpretable kinase signatures that are readily integrated with genomic, transcriptomic, and phenotypic readouts to generate and prioritize actionable hypotheses. The novelty of the Kinase Library is twofold. First, scope and provenance: an experimental, unbaised atlas spanning the entire kinome, with comprehensive inclusion of the dark kinome. Second, operationalization: a unified enrichment paradigm that yields robust, rank-ordered kinase programs suitable for decisionmaking — whether the objective is target nomination, combination design, biomarker discovery, or comparative benchmarking across cohorts and studies. Looking forward, the Kinase Library is positioned to empower emerging frontiers in proteomics: single-cell and spatial phosphoproteomics; longitudinal “N-of-1” monitoring to guide therapy; cross-species translation for model selection; and cloudnative workflows that interoperate with community pipelines and public datasets. By elevating kinases from disparate lists of regulated sites to coherent, testable signaling hypotheses, the Kinase Library reframes what phosphoproteomics can deliver — shifting the field from descriptive measurement toward predictive, mechanism-guided intervention. Citation Format: Tomer M. Yaron-Barir, Jared L. Johnson, Benjamin E. Turk, Michael B. Yaffe, Lewis C. Cantley. The Kinase Library: A global atlas of the human protein kinome and its applications in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1331.

  PublisherDOI

• Abstract 1547: IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma

  Cancer Research · 2026-04-03

  article

  Abstract Oncolytic virotherapy represents a promising yet under-explored therapeutic avenue for precision cancer treatment, particularly when tailored to tumor-specific molecular alterations. Patients with high-grade IDH-mutant astrocytomas continue to face limited treatment options and poor outcomes, emphasizing the need for novel strategies. In this study, we evaluated the therapeutic potential of rQNestin34.5v.2, an engineered oncolytic HSV-1, in the context of IDH1-R132H-mutant high-grade diffuse gliomas. We show that the IDH1-R132H mutation increases glioma susceptibility to viral infection by upregulating Nectin-1, the main HSV-1 entry receptor in gliomas. Concurrently, IDH1-R132H-driven DNA hypermethylation suppresses interferon (IFN) signaling, an essential antiviral defense pathway, creating a permissive environment that supports enhanced viral replication and increases tumor cell sensitivity to virus-induced apoptosis. In immunocompetent IDH1-R132H murine glioma models, intratumoral delivery of rQNestin34.5v.2 induced robust immune activation, marked by increased immune-cell infiltration into the tumor and systemic release of IFN-γ. However, elevated expression of poliovirus receptor (PVR-CD155) and the inhibitory immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on tumor-infiltrating lymphocytes, suggested the emergence of an adaptive resistance mechanism following virotherapy. Combining rQNestin34.5v.2 with TIGIT blockade enhanced therapeutic efficacy and improved survival outcomes compared to monotherapy. Collectively, these data demonstrate that IDH1-R132H reshapes both viral entry pathways and antiviral immune defenses, identifying it as a predictive biomarker for oncolytic virotherapy response. Citation Format: Eleni Panagioti, Hunter J. Kelley, Alexander L. Ling, William Goins, Daniel Roberts, Sotiris Sotiriou, Bryan J. Iorgulescu, Karen Dixon, Michael B. Yaffe, Maria G. Castro, Sean E. Lawler, Gordon J. Freeman, Vijay K. Kuchroo, E Antonio Chiocca, Charles H. Cook. IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1547.

  PublisherDOI

• A Legacy of Mentorship: A Tribute to Lewis Cantley

  Cancer Discovery · 2026-03-02

  articleSenior author
  PublisherDOI

• Supplementary Movie S6 from Plk1 Inhibitors and Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling

  2025-11-24

  articleOpen accessSenior author

  <p>Normal mitotic cell division</p>

  PublisherDOI

• Supplementary Table S3 from Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth

  2025-11-03

  articleOpen access

  <p>GCN1 cDNA sequence in 4964-POP and 4964-HOP cells.</p>

  PublisherDOI

• Supplementary Figure S7 from Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth

  2025-11-03

  articleOpen access

  <p>Figure S7. Expression of IMPACT is lost through genomic deletion and epigenetic silencing</p>

  PublisherOA PDFDOI

• Data from Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth

  2025-11-03

  articleOpen access

  <div>Abstract<p>Given the propensity of aggressive epithelial tumors to form hepatic metastases, we performed an <i>in vivo</i> cDNA screen using the mouse liver and <i>KRAS</i><sup>G12D</sup>/<i>TP53</i><sup>R273H</sup> pancreatic cells that identified the RNA-binding protein GCN1 as an integral component of hepatic outgrowth. RNAi experiments reveal that GCN1 triggers the integrated stress response (ISR) to activate serine, folate, and methionine biosynthetic pathways together with amino acid transporters, which act in concert to facilitate acquisition of metabolites and to restore redox homeostasis. Alongside the activation of the ISR, we found that GCN1 also functions in the nucleus where it interacts with HNRNPK to suppress the expression of MHC-I molecules and NK ligands. Intriguingly, we identified IMPACT as an endogenous competitive inhibitor of GCN1 that blocks both ISR-dependent metabolic control and disrupts HNRNPK interaction. In doing so, IMPACT enhances tumor immunogenicity to unleash NK cell killing, in addition to sensitizing metastatic tumor cells to immune checkpoint blockade.</p>Significance:<p>Metastatic tumor cells display profound immunometabolic plasticity to colonize distant organs. We identify IMPACT, an inhibitor of GCN1-stress signaling, expression of which curtailed metabolic plasticity and augmented tumor immunogenicity, sensitizing metastatic tumor cells to NK cell–mediated destruction.</p></div>

  PublisherDOI

• Supplementary Figure S3 from Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth

  2025-11-03

  articleOpen access

  <p>Figure S3. IMPACT limits ATF4 activation through competitive inhibition of GCN1</p>

  PublisherOA PDFDOI

• Supplementary Movie S4 from Plk1 Inhibitors and Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling

  2025-11-24

  articleOpen accessSenior author

  <p>Identification of paired centromeres from sister chromatids</p>

  PublisherDOI

Recent grants

• NIH Grant R21CA109661

  NIH · $284k · 2007

• Modeling human phosphorylation networks through kinome-wide profiling

  NIH · $2.4M · 2013–2018

• RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies

  NIH · $2.7M · 2018–2024

• NIH Grant R21ES020466

  NIH · $437k · 2016

• NIH Grant R01GM059281

  NIH · $4.5M · 2013

Frequent coauthors

• Christopher D. Barrett

  318 shared

• Ernest E. Moore

  University of Colorado Denver

  199 shared

• Brian A. Joughin

  Massachusetts Institute of Technology

  180 shared

• Hunter B. Moore

  University of Colorado Anschutz Medical Campus

  162 shared

• Carl J. Hauser

  Harvard University

  141 shared

• Brahm H. Segal

  University at Buffalo, State University of New York

  141 shared

• Leo E. Otterbein

  Beth Israel Deaconess Medical Center

  141 shared

• Tiffany R. Emmons

  Roswell Park Comprehensive Cancer Center

  132 shared

Awards & honors

• MacVicar Faculty Fellow, 2021
• Fellow, Association of American Physicians, 2021
• Teaching with Digital Technology Award, 2018