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Immunogenic cell death (ICD) is a vital component of therapeutically induced anti‐tumor immunity. An iridium(III) complex (Ir1), containing an N,N‐bis(2‐chloroethyl)‐azane derivate, as an endoplasmic reticulum‐localized ICD inducer for non‐small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage‐associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1‐treated dying cells elicited an antitumor CD8+ T cell response and Foxp3+ T cell depletion, which eventually resulted in long‐acting anti‐tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir‐based complex that is capable of developing an immunomodulatory response by immunogenic cell death.

As an effective and noninvasive treatment of various diseases, photodynamic therapy (PTD) relies on the combination of light, a photosensitizer, and oxygen to generate cytotoxic reactive oxygen species that can damage malignant tissue. Much attention has been paid to covalent modifications of the photosensitizers to improve their photophysical properties and to optimize the pathway of the photosensitizers interacting with cells within the target tissue. Herein we report the design and synthesis of a supramolecular heterometallic Ru-Pt metallacycle via coordination-driven self-assembly. While inheriting the excellent photostability and two-photon absorption characteristics of the Ru(II) polypyridyl precursor, the metallacycle also exhibits red-shifted luminescence to the near-infrared region, a larger two-photon absorption cross-section, and higher singlet oxygen generation efficiency, making it an excellent candidate as a photosensitizer for PTD. Cellular studies reveal that the metallacycle selectively accumulates in mitochondria and nuclei upon internalization. As a result, singlet oxygen generated by photoexcitation of the metallacycle can efficiently trigger cell death via the simultaneous damage to mitochondrial function and intranuclear DNA. In vivo studies on tumor-bearing mice show that the metallacycle can efficiently inhibit tumor growth under a low light dose with minimal side effects. The supramolecular approach presented in this work provides a paradigm for the development of PDT agents with high efficacy.

A series of mitochondria-targeting cyclometalated iridium(iii) complexes activated the oncosis-specific protein porimin and calpain 1, and exhibited good inhibitory activities on a wide range of cancer types including drug-resistant cancers.