MEMP PhD Thesis Defense: Yuzhou Evelyn Tong

From Observation to Perturbation: Dissecting Cell State Transitions in Immune and Cancer Cells

Cell state transitions are central to both immune function and disease progression, yet the mechanisms that govern these transitions and their therapeutic implications remain poorly understood. This thesis bridges observational and perturbational approaches to dissect how immune and cancer cells acquire, maintain, and functionally leverage dynamic transcriptional states.

In the first part, I applied scRNA-seq across multiple biological contexts to characterize immune cell states. In hematologic malignancy, we identified that myeloid dysfunction driven by inhibitory signals can occur at the pre-malignant stage but is reversible with therapy. Using an in vivo colon cancer model, we demonstrated that activating myeloid cells with a TLR7/8 agonist can restore antitumor immunity. Extending beyond cancer, we investigated how influenza vaccination and pneumococcal colonization jointly shape lung immunity, finding that these exposures can destabilize the macrophage homeostasis in the lower respiratory tract. Together, these studies highlight that immune cell state transitions are dynamic, context-dependent and functionally relevant. However, they only reveal correlations with clinical outcomes, without identifying the drivers of these transitions or their functional consequences.

To address these limitations, in this defense, I will discuss the second part of the thesis, which introduces a high-throughput experimental and computational framework for mapping cell states to functions. Using pooled transcription factor (TF) overexpression, positive selection screens, and multiplexed scRNA-Seq, I identified diverse adaptive states that enhance cancer fitness under inflammatory and therapeutic pressures. In IFNg screens modeling inflammation, distinct TFs induced different tolerant states, with the strongest phenotypes arising from a coordinated suppression of antiviral ISGs and activation of stress-adaptive programs. In KRAS inhibitor screens, non-genetic resistance was induced by coordinated activation of multiple stress-adaptive and pro-survival programs, with HNF1A/1B emerging as potent drivers. Notably, TF-induced states by HNF1A and HAND2 conferred broad cross-resistance to MAPK inhibitors and inflammatory cytokine, revealing how specific cell states promote survival under diverse environmental pressures. By linking transcription factors to cell state transitions and functional consequences, this platform moves beyond observational transcriptomics toward function-guided, and actionable insights.

Thesis Supervisor:
Alex K. Shalek, Ph.D.
Director, Institute for Medical Engineering & Science, MIT
Director, Health Innovation Hub
J. W. Kieckhefer Professor, Department of Chemistry, Institute for Medical Engineering & Science, and Koch Institute, MIT

Thesis Committee Chair:
Bryan Bryson, Ph.D.
Associate Professor, Department of Biological Engineering, MIT

Thesis Readers:
Catherine J. Wu, MD
Professor of Medicine, Dana-Farber Cancer Institute (DFCI) and Harvard Medical School
Chief of the Division of Stem Cell Transplantation and Cellular Therapies, DFCI

Srivatsan Raghavan, MD, Ph.D.
Assistant Professor of Medicine, Harvard Medical School

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Zoom Invitation
Evelyn Tong is inviting you to a scheduled Zoom meeting

Topic: Evelyn Tong MEMP PhD Thesis Defense
Time: Tuesday, December 2, 2025, 9:30 AM Eastern Time (US and Canada)

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