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Target Profiling of an Iridium(III)-Based Immunogenic Cell Death Inducer Unveils the Engagement of Unfolded Protein
Xiaolin Xiong1, Ke-Bin Huang2, Yuan Wang1
1Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
Abstract:
Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex (1a) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a, the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.
Insights
A new iridium complex induces immunogenic cell death (ICD) by engaging BiP/GRP78, a key protein in the unfolded protein response. This discovery advances understanding of ICD mechanisms and aids in designing novel chemo-immunotherapies.
Area of Science:
- Biochemistry
- Immunology
- Materials Science
Background:
- Chemotherapeutic drugs can trigger antitumor immune responses beyond direct cancer cell killing, a phenomenon known as immunogenic cell death (ICD).
- Despite the promise of chemo-immunotherapy, the number of identified ICD inducers and their precise drug-target interactions remain limited.
- Understanding the molecular mechanisms underlying ICD is crucial for developing more effective cancer treatments.
Purpose of the Study:
- To identify novel chemical entities capable of inducing immunogenic cell death (ICD).
- To elucidate the molecular targets and mechanisms of action for a newly developed cyclometalated Iridium(III)-bisNHC complex (1a) as an ICD inducer.
- To explore the role of the identified target in the broader context of ICD induction by various chemotherapeutic agents.
Main Methods:
- Synthesis and characterization of a novel endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex (1a).
- Design and application of a clickable photoaffinity probe for target identification of compound 1a.
- Utilized fluorescence microscopy, cellular thermal shift assay (CETSA), and enzymatic assays to confirm target engagement and functional effects.
Main Results:
- Compound 1a was identified as a novel inducer of immunogenic cell death (ICD).
- Target identification revealed that 1a engages BiP (binding immunoglobulin protein)/GRP78, a central regulator of the unfolded protein response.
- Cellular and biochemical studies confirmed 1a's ability to destabilize BiP.
- Existing ICD inducers (KP1339, mitoxantrone, oxaliplatin) also showed interaction with BiP, highlighting its potential role in ICD.
Conclusions:
- A novel cyclometalated Iridium(III)-bisNHC complex (1a) effectively induces immunogenic cell death (ICD) through endoplasmic reticulum stress.
- BiP/GRP78 is identified as a key molecular target for compound 1a and potentially for other ICD inducers.
- This research provides valuable insights into the mechanism of ICD and offers a foundation for designing next-generation chemo-immunotherapeutic agents with enhanced specificity and efficacy.
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