Our research in bioorthogonal therapeutics aims to bridge the gap between chemical biology and precise therapeutics to overcome the fundamental limitations of current pharmacotherapies. Through our pioneering work in Multi-TACs, membrane protein degradation, and bioorthogonal pro-therapeutics, we are creating programmable medicines that can simultaneously engage multiple immune cells, selectively eliminate disease-driving proteins for cancer and autoimmune diseases.
Recent representative work:
1) T-Linker technology and Multi-TACs
Multi-specific medicines have recalibrated expectations of what can be achieved through pharmacotherapy, while a universal construction platform for diverse modalities (e.g., Bispecific antibodies, ADCs, PROTACs) is still lacking, given the profound heterogeneity of the molecular entities involved. To address these, our lab has developed a triple orthogonal linker (T-Linker)-based platform that enables the programmable integration of multiple and diverse therapeutic modules into single agents via triple orthogonal conjugations. Multimodal targeting chimeras (Multi-TACs) that integrate tumor-targeting, lymphocyte-engaging, and myeloid-engaging modules were developed to support tumor-localized co-engagement of multiple immune cells in the TIME, resulting in potent antitumor activity (Cell 2024). T-Linker technology constitutes a modular pharmacological platform that (1) enables the precise fabrication of multi-specific molecules and (2) may effectively circumvent the obstacles inherent in the simultaneous delivery of multiple therapeutic agents. Multi-TACs (1) represent a novel pharmacological entity for coordinated multiple immune cell antitumor immunity, and (2) may serve as molecule tools for manipulation of multicellular systems
2) MeTPD and related targeted degradation of membrane proteins:
Membrane proteins are key players in cellular interactions and cell signaling, differentiation and proliferation, stress response and other life processes. They directly influence the development of many diseases including malignant tumors and neuropathic pain, and are an important class of drug targets. However, conventional drugs act by blocking the interaction of the extracellular region of membrane proteins with ligands or inhibiting the activity of their intracellular regions, which often suffer from incomplete inhibition or induce drug resistance. To address this problem, our team developed a mass spectrometry-based covalent single-domain antibody (GlueBody) screening method and obtained GlueBody targeting PD-L1, which led to the development of a universal membrane protein degradation technology, GlueTAC, which provides a powerful tool for eliminating abnormal membrane proteins and can overcome the problem of drug resistance due to long-term drug use (JACS, 2021) . To further enhance the selectivity of membrane protein degradation in tumor cells, we employed a masking peptide strategy to develop Pro-MPD, a technology enabling tumor-microenvironment-responsive membrane protein degradation (JACS, 2024) . Moving beyond general selectivity, we aimed to target complex cellular systems—specifically the immune system. By leveraging CD22, a B-cell-specific marker, as a 'handle,' we achieved targeted membrane protein degradation on B lymphocytes without affecting the functions of other cell types for autoimmune diseases (JACS, 2025). Furthermore, we utilized membrane protein degradation strategies to reprogram tumor cells. By introducing a universal antigen and simultaneously degrading PD-L1, we successfully recruited bystander T cells, achieving effective tumor cell reprogramming and elimination (Nature 2025; Science 2025)
3) Bioorthogonal Pro-therapeutics
Dose-limiting toxicity is a fundamental problem in all cancer treatments including antibody-drug conjugates (ADCs), since systemically administered agents distribute throughout human body rather than selectively accumulating at tumor sites. A promising strategy to overcome the limitation is to achieve precise and spatially-confined activation of the drug's activity exclusively within tumor tissues. Our laboratory is dedicated to developing Tumor-targeted Bioorthogonal Pro-therapeutics that precisely control drug activity through highly efficient bioorthogonal cleavage reactions, while achieving tumor-specific accumulation via a pre-targeting strategy (Nat Commun. 2018; CCS Chem. 2019; Bioconjugate Chem. 2023). As a universal platform, our strategy is compatible with various targeting modalities (e.g. antibodies, peptides, and small-molecule ligands), and can be readily extended to diverse therapeutic agents, enabling the creation of pro-chemotherapies, pro-cytokines, and pro-bodies. By maximizing active drug concentrations at the tumor site while minimizing systemic exposure, our technology holds the potential to expand the therapeutic scope of current anti-tumor drugs such as ADCs and immunotherapies.
Representative publications：
1. Han Y, Ma Y, Pei M, Yin S, Wang J, Guo L, Fang Y, Guo W, Deng C, Zhao S, Lu X, Xi J*, Zhang H*, Chen P*, “Intratumoral vaccine by checkpoint degradation-coupled antigen presentation”, Nature 2026, 650, 736–747
2. Zhu R, Zhang H*, Chen P*, “Targeted protein degradation in the transmembrane and extracellular space”, Science 2025, DOI: 10.1126/science.adx5094
3. Lin F, Yin S, Zhang Z, et al. and Chen P* Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment. Cell 2024, 187(26): 7470-7491. e32.
4. Yang Z, Jiang J,Cao Y, Fang H, Zhang X, Zhang Y, Zhang H*, and Chen P* Cell-selective Targeting Chimeras (SelecTACB) for membrane protein degradation on B cells. J. Am. Chem. Soc. 2025, 147, 40, 36301–36309
5. Liu H, Fu Z, Han Y, Fang Y, Shen W, Chen Z, Zhu R, Zhang H*, Chen P*, “Conditionally activatable chimeras for tumor-specific membrane protein degradation”, J. Am. Chem. Soc. 2024 ,146, 32933-41.
6. Zhang H, Han Y, Yang Y, Lin F, Lin J*, Chen P*.“Covalently engineered nanobody chimeras for targeted membrane protein degradation”.J. Am. Chem. Soc. 2021, 143, 16377-82
7. Yao Q, Lin F, Fan X, et al. and Chen P* Synergistic enzymatic and bioorthogonal reactions for selective prodrug activation in living systems. Nature communications 2018, 9(1): 5032.
8. Lin F, Chen L, Zhang H, et al. and Chen P* Bioorthogonal prodrug–antibody conjugates for on-target and on-demand chemotherapy. CCS Chemistry, 2019: 226-236.
9. Yao Q, Lin F, Lu C, et al. and Chen P* A dual-mechanism targeted bioorthogonal prodrug therapy. Bioconjugate chemistry, 2023, 34(12): 2255-2262.
