Research
The central goal of our laboratory is to understand how immune cell function is shaped by dynamic protein regulation and intercellular communication, and to harness these principles to develop next-generation immunotherapies. Our work integrates immune engineering and genome editing to interrogate and rewire immune signaling across molecular, cellular, and tissue scales.
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Pillar I: Immune engineering through dynamic control of immune signaling
1. Harnessing cell-endogenous machinery to engineer synthetic receptors
Cell-based immunotherapies, particularly CAR-T cells, have demonstrated transformative clinical potential. However, durable responses remain limited, in part because current CAR designs do not recapitulate the dynamic regulatory mechanisms that govern endogenous immune receptors. While the T cell receptor (TCR) is tightly regulated through processes such as internalization, recycling, and motif-dependent control, CARs have largely been treated as static signaling modules.
​​​​​​​​In our published work, we demonstrated that CAR function can be systematically tuned by incorporating endogenous regulatory elements that control receptor dynamics. By introducing cytoplasmic regulatory motifs derived from immune checkpoint receptors into CAR constructs, we showed that receptor behavior—including antigen acquisition, fratricide, and functional persistence—could be predictably modulated, resulting in substantially improved anti-tumor efficacy in vivo (Zhou et al., Nature Immunology, 2023). This work established that engineering receptor dynamics, rather than only downstream signaling domains, represents a powerful and underexplored axis for immune cell design.
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2. Reprogramming intercellular immune communication
Building on these principles, ongoing work in the lab extends beyond cell-intrinsic receptor regulation to investigate how immune cell behavior is shaped by direct interactions with other cells in complex tissue environments. Rather than focusing solely on blocking suppressive pathways, we are exploring strategies to reprogram intercellular signaling itself, redirecting inhibitory or dysfunctional immune cues toward productive activation. By leveraging endogenous immune regulatory processes, this work aims to establish generalizable approaches for rewiring immune communication at the level of cell–cell interactions, with broad implications for improving immune function in solid tumors and other disease contexts.
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Pillar II: Gene editing to decode intercellular immune communication
1. Foundational platforms for network-level immune interrogation
A complementary direction in the lab focuses on developing genome editing approaches to dissect how immune cells communicate with one another and with their tissue environment. Because intercellular immune communication is governed by coordinated activity of multiple regulators across interacting cell types, understanding these processes requires experimental systems that move beyond single-gene perturbations.
Our previous work has contributed CRISPR-based genetic technologies that enable systematic interrogation of immune regulators in physiologically relevant settings. Early studies demonstrated how targeted genetic perturbations can reveal immune pathways controlling anti-tumor responses. Building on this foundation, we developed genome editing platforms that enable simultaneous perturbation of multiple immune genes within the same cell in vivo, allowing functional analysis of gene–gene interactions during immune responses (Tang*, Zhou*, et al., Nature Biomedical Engineering, 2025). These tools provide a foundation for examining immune behavior as an emergent property of interacting regulatory networks rather than isolated pathways.
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2. Uncovering principles of immune communication
Ongoing efforts in the lab use genetic perturbation strategies to systematically probe how immune cells interpret and respond to various signals. Rather than focusing on individual pathways, this work seeks to uncover higher-order principles that govern immune communication and functional state transitions. By integrating network-level perturbation with functional measurements of immune behavior, the lab aims to identify general mechanisms that shape intercellular immune interactions and inform the development of novel immunotherapeutic strategies.
