Synergization of an endoplasmic reticulum-targeted iridium(III) photosensitizer with PD-L1 inhibitor for oral squamous cell carcinoma immunotherapy

{"full_text": " Chemical Engineering Journal 474 (2023) 145516\n\n\n Contents lists available at ScienceDirect\n\n\n Chemical Engineering Journal\n journal homepage: www.elsevier.com/locate/cej\n\n\n\n\nSynergization of an endoplasmic reticulum-targeted iridium(III)\nphotosensitizer with PD-L1 inhibitor for oral squamous cell\ncarcinoma immunotherapy\nJia-Ying Zhou a, b, 1, Qing-Hua Shen c, 1, Xiao-Jing Hong a, b, 1, Wu-Ya Zhang a, b, Qiao Su d,\nWu-Guo Li d, Bin Cheng a, b, *, Cai-Ping Tan c, *, Tong Wu a, b, *\na\n Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, PR China\nb\n Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510080, PR China\nc\n MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou 510006, PR China\nd\n Animal Experiment Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China\n\n\n\n\nA R T I C L E I N F O A B S T R A C T\n\nKeywords: Inefficient activation of tumor immunogenicity and sustained immunosuppressive microenvironments severely\nIridium impede the clinical application of photodynamic therapy (PDT) in oral squamous cell carcinoma (OSCC). Herein,\nEndoplasmic reticulum two type I/II iridium(III) photosensitizers (Ir1 and Ir2) targeting endoplasmic reticulum (ER) are designed as\nImmunogenic cell death\n immunogenic cell death (ICD) inducers. Ir1-meidated PDT treatment adaptively upregulates the programmed\nImmune checkpoint inhibitors\nImmunotherapy\n death-ligand 1 (PD-L1) expression in vitro. Moreover, Ir1-mediated PDT stimulates dendritic cell maturation, T\nOral squamous cell carcinoma lymphocyte infiltration and antitumor cytokine secretion, and synergizes with PD-L1 inhibitor to transform\n immune-suppressive \u201ccold tumor\u201d to immune-responsive \u201chot tumor\u201d in vivo. Our study firstly paves the way for\n the combination of metal-based photosensitizing ICD inducer with PD-L1 inhibitor for enhanced immunotherapy.\n\n\n\n\n1. Introduction oxygen species (ROS) production through both type I/II pathway and\n even oxidation of biomolecules [12\u201316].\n Photodynamic therapy (PDT) is an effective modality for cancer Endoplasmic reticulum (ER) is responsible for crucial biosynthesis,\ntherapy due to its noninvasiveness, spatiotemporal precision and high sensing and signaling functions in eukaryotic cells [17]. Therefore, se\u00ad\ncontrollability [1]. Besides direct cytotoxicity, PDT can also induce lective disruption of ER function in cancer cells is a promising strategy\nimmunogenic cell death (ICD) of tumor cells to promote antitumor im\u00ad for anticancer therapy [18]. Especially, ER-targeting chemotherapeutic\nmunity [2]. ICD can trigger damage-associated molecular patterns agents and PSs are proved to be potent ICD inducers by destroying ER\n(DAMPs) of tumor cells, subsequently induce the maturation of dendritic protein-folding capacity leading to excessive or aberrant ER stress\ncells (DCs) and therefore activate the systemic antitumor immune re\u00ad [19,20]. Recent studies show that metal complexes are promising\nsponses [3,4]. Although cisplatin and oxaliplatin remain the classical organelle-targeting ICD-inducing PSs for antitumor immunotherapy in\nchemotherapy agents for many types of cancer including oral squamous melanoma, breast cancer and hepatocellular carcinoma [21\u201323].\ncell carcinoma (OSCC), researches indicate that they both fail to induce Notably, ICD inducer monotherapy fails to confer sufficient benefit\nrobust ICD [5,6]. Metal-based photosensitizers (PSs) have revealed sig\u00ad in many cases, because tumor cells may adaptively upregulate pro\u00ad\nnificant potential as novel anticancer therapeutic agents [7,8]. Signifi\u00ad grammed death-ligand 1 (PD-L1) expression to evoke tumor self-\ncantly, ruthenium and iridium complexes have been proven to be protective mechanism after treatment, which further aggravates the\nefficient ICD inducers [9\u201311]. Especially, by exquisite structural modi\u00ad immunosuppressive tumor microenvironment (TME) and impedes\nfications, iridium complexes show interesting PDT properties including infiltration and activation of effector T cells [24,25]. Immune check\u00ad\nspecific subcellular targeting, high photo-stability, efficient reactive point inhibitors (ICIs) involving programmed death protein 1 (PD-1)\n\n\n * Corresponding authors at: Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, PR China (Bin Cheng, Tong\nWu); MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou 510006, PR China (Cai-Ping Tan).\n E-mail addresses: chengbin@mail.sysu.edu.cn (B. Cheng), tancaip@mail.sysu.edu.cn (C.-P. Tan), wutong23@mail.sysu.edu.cn (T. Wu).\n 1\n These authors contributed equally to this work.\n\nhttps://doi.org/10.1016/j.cej.2023.145516\nReceived 27 May 2023; Received in revised form 21 July 2023; Accepted 16 August 2023\nAvailable online 17 August 2023\n1385-8947/\u00a9 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-\nnc-nd/4.0/).\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\nand PD-L1 have received extensive attention due to their regulatory is a possibility to develop a paradigm combining metal-based ICD in\u00ad\nfunction between T cells and tumor cells [26]. However, the respon\u00ad ducers with ICIs for enhanced cancer photoimmunotherapy, the corre\u00ad\nsiveness of PD-1/PD-L1 blockade monotherapy only ranged from 13% to lation and synergistic mechanisms between the two treatment methods\n18% in OSCC [27,28]. ICIs monotherapy provokes unsatisfactory anti\u00ad are not yet clear.\ntumor effects in most patients. The main reason is that the majority of Herein, we designed two cyclometalated iridium(III) complexes (Ir1\ncancer patients have \u201ccold tumors\u201d with defect of antigen presentation, and Ir2) with a phenanthroline ligand modified with a hydrophobic\nabsence of T cell infiltration and activation that do not respond to long-chain N-phenethylsuccinamide moiety as potent ER-targeted type\nexisting immunotherapeutic agents [29,30]. Besides, PD-L1 inhibitors I/II PSs. Ir1 selectively accumulates in ER by interacting with the\nare only effective for PD-L1 positive patients, while the expression of PD- phospholipids and proteins, induces ROS generation through both type\nL1 varies between individuals [31,32]. Therefore, simultaneously I/II PDT pathways and elicits ER stress under visible light (425 nm)\nincreasing immunogenicity by ICD inducers and relieving immunosup\u00ad irradiation. Meanwhile, Ir1 leads to release of DAMPs to induce ICD for\npression via ICIs are promising strategies to reverse TME from immu\u00ad enhanced tumor immunogenicity, while in parallel Ir1 upregulates the\nnosuppressive \u201ccold\u201d to immunogenic \u201chot\u201d to elicit efficient immune expression of PD-L1 in OSCC cells. Moreover, cell-derived xenograft\nresponses. Recent clinical studies have demonstrated an enhanced (CDX) and oral experimental carcinogenesis models demonstrate that\ntherapeutic response as well as long-term protection of individuals upon Ir1-mediated PDT synergizing PD-L1 immunotherapy elicits robust im\u00ad\nco-treatment with the carboplatin and pembrolizumab or co-treatment mune responses through the infiltration of DCs and T lymphocytes, the\nwith the cisplatin and nivolumab [33\u201335], which highlights the prom\u00ad secretion of antitumor cytokines and the attenuation of immunosup\u00ad\nising synergistic potential of the combination treatment. Although, there pressive TME, which converts the immune \u201ccold tumor\u201d into \u201chot\n\n\n\n\nScheme 1. (A) Chemical structures of Ir1 and Ir2. (B) Schematic diagram of Ir1 and Ir2 as type I/II PSs. (C) Ir1-mediated PDT evokes ROS-induced ER stress, and\nreleases DAMPs to cause ICD for enhanced tumor immunogenicity. Moreover, PDT acts synergistically in combination with the PD-L1 inhibitor to promote the\nantigen presentation of DCs, infiltration of T lymphocytes, secretion of antitumor cytokines and response to ICIs therapy, thereby converting the \u201ccold tumor\u201d into\n\u201chot tumor\u201d to elicit potent antitumor immune responses. CDX: cell-derived xenograft; 4NQO: 4-nitroquinoline-1-oxide; ROS: reactive oxygen species; ER: endo\u00ad\nplasmic reticulum; eIF2\u03b1: eukaryotic initiation factor 2 alpha; CHOP: C/EBP homologous protein; CRT: calreticulin; ATP: adenosine triphosphate; HMGB1: high\nmobility group box-1 protein; PD-1: programmed death protein 1; PD-L1: programmed death ligand 1; ICD: immunogenic cell death; DCs: dendritic cells; TNF-\u03b1:\ntumor necrosis factor-\u03b1; IFN-\u03b3: interferon-\u03b3.\n\n 2\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\ntumor\u201d (Scheme 1). As far as we know, it is the first report on the (Fig. 1B). Electron spin resonance (ESR) using 2,2,6,6-tetramethyl-4-\nexploration of the synergetic immunomodulatory properties of metal- piperidone (TEMP) as the trapping agent proves the photosensitizing\nbased ICD PSs and PD-L1 inhibitor, which paves the way for the generation of 1O2 by Ir1 and Ir2 (Fig. 1C and Fig. S13). Moreover, ESR\nfuture clinical transformation of the metal-based PSs for photo\u00ad measurement using 5,5-dimethylpyrroline N-oxide (DMPO) as the\nimmunotherapy in OSCC. trapping agent confirms the production of \u2022OH by Ir1 and Ir2 in the\n presence of light (Fig. 1D and Fig. S14). Moreover, detection of \u2022OH by\n2. Results and discussion hydroxyphenyl fluorescein (HPF) further confirms the photosensitizing\n generation of \u2022OH by Ir1 and Ir2 (Fig. S15). These results collectively\n2.1. Synthesis and characterization show that the ROS (1O2 and \u2022OH) generation capacity of Ir1 is higher\n than that of Ir2.\n Ir1 and Ir2 were synthesized by reacting the precursor [Ir(N\u2013N)2Cl]2 To gain insight into the geometric and electronic properties of Ir1\n(C^N = 2-phenylpyridine (ppy; Ir1); 2-(2,4-difluorophenyl)pyridine and Ir2, density-functional theory (DFT) and time-dependent density-\n(dfppy; Ir2)) with the N1-(1,10-phenanthrolin-5-yl)-N4-phenethylsucci\u00ad functional theory (TDDFT) calculations were performed at the\nnamide (L) and purified by silica chromatography (Scheme S1). Ir1 and PBE1PBE/6-31G*//LanL2DZ level. The highest occupied molecular\nIr2 were characterized by 1H NMR, 13C NMR, 19F NMR, ESI-MS and orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO)\nHPLC (Figs. S1\u2013S11). The absorption spectra of Ir1 and Ir2 feature high- energy levels of Ir1 are \u2212 6.26 eV and \u2212 2.61 eV, respectively, and the\nenergy bands (<350 nm; ligand-centered (1LC) \u03c0\u2013\u03c0* transitions) and gap of HOMO-LUMO of Ir1 is 3.65 eV (Fig. 1E). The energy gap between\nrelatively low-energy bands (mixed metal-to-ligand charge-transfer the singlet state and triplet state (\u0394Es\u2013t) of Ir1 is 0.29 eV (Fig. 1F). The\n(MLCT) and ligand-to-ligand charge-transfer (LLCT) transitions; Fig. 1A HOMO and LUMO of Ir2 are \u2212 6.56 eV and \u2212 2.71 eV, respectively. The\nand Fig. S12). Ir1 and Ir2 exhibit orange-red phosphorescent emissions gap of HOMO-LUMO is 3.85 eV, and the \u0394Es\u2013t of Ir2 is 0.37 eV (Fig. S16).\nupon excitation at 405 nm (Fig. 1A and Fig. S12). Considering the su\u00ad The higher capability of Ir1 as a type I and type II PDT agent can be\nperficial site of OSCC, the 425 nm laser is selected to irradiate iridium explained by its smaller \u0394Es\u2013t and better electron-donating ability,\ncomplexes to perform PDT. The emission quantum yields of Ir1 and Ir2 which is important for the production of \u2022OH [36,37].\nin PBS, CH3CN and CH2Cl2 fall in the range between 0.019 and 0.146\n(Table S1).\n 2.2. Ir1 exerts potent photocytotoxicity in vitro\n The photocatalytic degradation of 9,10-anthracenediyl-bis(methy\u00ad\nlene)-dimalonic acid (ABDA, 1O2 probe) by Ir1 and Ir2 in the presence\n The photocytotoxicity effects of Ir1 and Ir2 in vitro were evaluated\nof light was evaluated in PBS. Using [Ru(bpy)3]Cl2 (0.18) as the stan\u00ad\n on human OSCC (CAL33, HSC6 and SCC1) and dysplasia oral kerati\u00ad\ndard, the 1O2 quantum yield of Ir1 and Ir2 are calculated to be 0.12 and\n nocyte (DOK) cell lines by Cell Counting Kit-8 (CCK-8) assay (Table 1\n0.06, respectively, indicating that Ir1 has a stronger ability to induce 1O2\n and Table S2). Ir1 and Ir2 show a lower dark cytotoxicity than cisplatin\n\n\n\n\nFig. 1. Ir1 and Ir2 can generate 1O2 and \u2022OH in the presence of light. (A) UV\u2013Vis absorption spectra and emission spectra (\u03bbex = 405 nm) of Ir1 and Ir2 (20 \u03bcM) in\nPBS. (B) The capability of Ir1 and Ir2 to photosensitize the generation of 1O2 using ABDA as the probe and [Ru(bpy)3]Cl2 as the standard. The solutions were\nirradiated with a 425 nm laser (20 mW cm\u2212 2) for different time intervals. (C) The ESR spectra of 1O2 generated by Ir1/Ir2 (100 \u03bcM) in the presence of light (20 mW\ncm\u2212 2, 3 min) using TEMP (10 mM) as the trapping agent. (D) The ESR spectra of \u2022OH generated by Ir1/Ir2 (100 \u03bcM) in the presence of light (20 mW cm\u2212 2, 5 min)\nusing DMPO (100 mM) as the trapping agent. (E) HOMO and LUMO of Ir1. (F) The mechanisms of Ir1 to generate ROS through both type I/II pathways. ILCT:\nintraligand charge-transfer.\n\n 3\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\nTable 1\nCytotoxicity (IC50, \u03bcM) of the tested compounds on OSCC cell lines.\n Compounds CAL33 HSC6 SCC1\n\n Dark Light PI Dark Light PI Dark Light PI\n\n Ir1 19.90 \u00b1 1.83 0.66 \u00b1 0.13 30.34 33.40 \u00b1 2.31 0.68 \u00b1 0.02 48.80 14.00 \u00b1 1.41 0.12 \u00b1 0.05 120.43\n Ir2 15.94 \u00b1 0.63 1.06 \u00b1 0.19 15.10 27.34 \u00b1 4.08 1.05 \u00b1 0.02 26.02 13.23 \u00b1 1.51 0.30 \u00b1 0.01 43.66\n Cisplatin 4.36 \u00b1 1.59 3.00 \u00b1 0.38 1.45 8.08 \u00b1 0.14 3.67 \u00b1 0.07 2.20 9.03 \u00b1 0.88 10.93 \u00b1 2.38 0.83\n\nIC50 value is the drug concentration necessary for 50% inhibition of cell viability. Cells were incubated with the tested compounds for 48 h and detected by CCK-8 assay\nin the absence and presence of 425 nm light (20 mW cm\u2212 2, 15 min). Phototoxicity index (PI) is defined as the ratio of darkIC50/lightIC50. Data are presented as the means\n\u00b1 standard deviations (SD) of three repeated measurements.\n\n\n\n\nFig. 2. Ir1 selectively targets ER and elicits ROS-induced ER stress upon PDT in vitro. (A) Emission spectra of Ir1 (10 \u03bcM) titrated with lecithin (0\u201370 \u03bcM) in Tris-HCl\nbuffer. Inset: The Benesi\u2013Hildebrand plot of 1/[I(600 nm)\u2013I0(600 nm)] against 1/[lecithin]. \u03bbex = 405 nm. (B) Emission spectra of Ir1 (10 \u03bcM) titrated with HSA (0\u201397.5\n\u03bcM) in Tris-HCl buffer. Inset: The Benesi\u2013Hildebrand plot of 1/[I(600 nm)\u2013I0(600 nm)] against 1/[HSA]. \u03bbex = 405 nm. (C) Confocal spectroscopic observation of co-\nlocalization of Ir1 (10 \u03bcM, 30 min) with ERTR (1 \u03bcM, 15 min) in SCC1 cells. Ir1: \u03bbex = 405 nm; \u03bbem = 620 \u00b1 20 nm. ERTR: \u03bbex = 561 nm; \u03bbem = 610 \u00b1 20 nm.\nScale bars: 10 \u00b5m. (D) Intracellular ROS levels measured by DCFH-DA staining via flow cytometry. SCC1 cells were incubated with Ir1 for 24 h and irradiated with a\n425 nm laser (20 mW cm\u2212 2, 15 min) before incubating with DCFH-DA (10 \u03bcM, 20 min). DCF: \u03bbex = 488 nm, \u03bbem = 525 \u00b1 20 nm. (E) The impact of Ir1-mediated PDT\non the expression of eIF2\u03b1, p-eIF2\u03b1 and CHOP by western blotting in SCC1 cells. Quantitative analysis of western blotting of three independent repeats was performed\nby ImageJ software. (F) TEM images of cell morphology upon PDT treatment by Ir1 (0.8 \u03bcM, 24 h) in the presence of a 425 nm laser (20 mW cm\u2212 2, 15 min). Scale\nbars: 5 \u00b5m and 2 \u00b5m. In panel D and E, data were shown as the mean \u00b1 SD of three biological replicates; ns, no significance; *p < 0.05, **p < 0.01, ***p < 0.001 and\n****p < 0.0001.\n\n 4\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\non all the cancer cell lines. Upon irradiation at 425 nm, Ir1 and Ir2 show results indicate that Ir1-mediated PDT induces ER stress via eIF2\u03b1-\npotent photocytotoxicity. Generally, the phototoxicity of Ir1 is higher dependent canonical pathway.\nthan that of Ir2, which is consistent with its high capability to generate Finally, the alterations in cell morphology upon Ir1 treatment were\nROS in vitro. Among the tested OSCC cell lines, SCC1 cells show the observed by transmission electron microscopy (TEM). Compared with\nhighest sensitivity to the PDT treatment, and the photocytotoxicity the control, cells treated with Ir1 (0.8 \u03bcM, 24 h) in combination with\nindex (PI) values of Ir1 and Ir2 in SCC1 cells are 120.43 and 43.66, light show typical ultrastructural characteristics of disrupted\nrespectively. In addition, the UV/Vis absorbance of iridium complexes is morphology including ER swelling and vacuolization (Fig. 2F).\nproportional to the concentration up to 100 \u03bcM (Fig. S17), which in\u00ad\ndicates that Ir1 and Ir2 can be completely dissolved at the working 2.4. Ir1-mediated PDT triggers ICD and adaptively upregulates PD-L1\nconcentrations. expression in vitro\n Due to the capability of Ir1 to generate O2-dependent 1O2 and O2-\nindependent \u2022OH, we also evaluated its PDT effects on cell lines under ER stress is considered to be a prominent factor in the induction of\nhypoxic conditions and 3D tumor spheroids simulating the hypoxic ICD [18,43]. Therefore, we investigated the ability of Ir1 to induce ICD\nTME. The phototoxicity of Ir1 is well maintained under hypoxia, and the in vitro. ICD can initiate immune response by the expression of DAMPs in\nPI values of Ir1 on SCC1 and SCC7 (murine squamous cell carcinoma cell dying tumor cells charactering with calreticulin (CRT) exposure, high\nline) cells are 95.24 and 30.22, respectively (Table S3). Moreover, Ir1- mobility group box-1 protein (HMGB1) migration and adenosine\ntreated SCC1 and SCC7 tumor spheroids in combination with light show triphosphate (ATP) secretion to achieve a long-term anticancer effect\nsignificantly diminished fluorescence, indicating Ir1 can penetrate the [44]. Flow cytometric results show an obvious concentration-dependent\n3D cellular architecture to eradicate tumor cells under hypoxic condi\u00ad increase of CRT on cell surface upon Ir1-mediated PDT treatment\ntion (Fig. S18). These results show that Ir1 can overcome the hypoxic (Fig. 3A). Meanwhile, cells with PDT treatment show apparent decrease\nTME by eliciting PDT through both type I and II pathways. of nuclear HMGB1, indicating the migration of HMGB1 from the nucleus\n to the extracellular region after treatment (Fig. 3B). Additionally, a dose-\n2.3. Ir1 selectively accumulates in ER and elicits ROS-induced ER stress dependent increase in the content of extracellular ATP is also detected\nupon PDT by chemiluminescence assay upon Ir1-mediated PDT treatment\n (Fig. 3C). However, both cisplatin and oxaliplatin fail to induce robust\n The cellular uptake and subcellular localization of metal-based ICD in OSCC cells (Fig. S21).\nagents are important factors influencing the anticancer efficacies [38]. Bioinformatic analysis indicates that CRT is significantly positively\nFirstly, cellular uptake mechanism of Ir1 has been investigated using correlated with PD-L1 expression in OSCC patients, which inspires us to\nconfocal laser scanning microscopy. Results indicate that tumor cells inquire whether Ir1 could promote the increase of PD-L1 (Fig. 3D).\npretreated with energy inhibitor and endocytic inhibitor or at low Surprisingly, upon Ir1-mediated PDT treatment, PD-L1 expression is\ntemperature show suppressed cellular luminescence, suggesting that Ir1 upregulated in a concentration-dependent manner by both real-time\nis uptaken by tumor cells mainly through an energy-dependent endo\u00ad quantitative polymerase chain reaction (RT-qPCR; Fig. 3E) and west\u00ad\ncytosis pathway (Fig. S19). ern blotting (Fig. 3F). HSF1\u2013HSP90 axis, NF-\u03baB and YAP1 signaling\n The long carbon chain and benzene ring at the end of the ligand in pathways may enhance the functional expression of PD-L1 after treat\u00ad\nour molecules are hydrophobic, which would be embedded into the ment with metallo-anticancer agents [45\u201347]. However, the exact\n\u201cnon-polar tail\u201d of phospholipid or hydrophobic cavities of protein. ER is mechanism of PD-L1 upregulation by ICD inducers remains unclear and\nthe largest organelle of the cell involved in lipid and protein synthesis needs to be further explored. These results show that Ir1-mediated PDT\n[39]. To verify our molecular design, we studied the binding of Ir1 to\u00ad can induce ROS-based ER stress to initiate ICD and adaptively upregu\u00ad\nwards lecithin (the prominent phospholipid of ER membrane) and lates PD-L1 expression.\nhuman serum albumin (HSA) as a model protein [40]. The emission\nintensity of Ir1 increases by 3-fold in the presence of lecithin accom\u00ad 2.5. Ir1-mediated PDT in combination with PD-L1 inhibitor inhibits oral\npanied by a slight blueshift in the emission maxima, and the Bene\u00ad carcinogenesis in 4NQO induced rat model\nsi\u2013Hildebrand binding constants (Kb) of Ir1 towards lecithin is\ncalculated to be 1.6 \u00d7 104 M\u2212 1 (Fig. 2A). Similarly, the titration results As Ir1-mediated PDT upregulates the expression of PD-L1 on tumor\nof Ir1 on HSA show that the emission intensity increases by almost 7- cells in vitro, which inspires us to propose the combination of PDT and\nfold in the presence of HSA and the Kb of Ir1 towards HSA is calcu\u00ad PD-L1 inhibitor for synergistic antitumor effects. Oral carcinogenesis is a\nlated to be 3.06 \u00d7 104 M\u2212 1 (Fig. 2B). Colocalization assay using the multistep evolutionary process from hyperplasia to dysplasia then car\u00ad\ncommercial subcellular organelle-specific staining probes shows that Ir1 cinoma in situ and finally invasive carcinoma, which provides a window\ncan well colocalize with ER-Tracker Red (ERTR) with a high Pearson\u2019s of opportunity for intervention [48]. BMS-1 is one of the small molecule\ncorrelation coefficient (PCC: 0.83 \u00b1 0.01; Fig. 2C), while it shows agents that can induce PD-L1 dimerization and thereby block the\nminimal colocalization with MitoTracker Deep Red (MTDR, PCC: 0.31 interaction with PD-1, which possesses many advantages such as ease of\n\u00b1 0.04) and LysoTracker Deep Red (LTDR, PCC: 0.44 \u00b1 0.05; Fig. S20). synthesis, high stability, improved tumor penetration, and low costs\nThese results indicate that Ir1 can target ER possibly by binding with the compared with monoclonal antibody [49,50]. The schematic illustration\nphospholipids and proteins. of establishment and experimental procedure for 4NQO induced oral\n We then assessed the capability of Ir1 to produce ROS upon light carcinogenesis rat model is shown in Fig. 4A. After the 16-week\nirradiation using 2\u2032,7\u2032-dichlorodihydrofluorescein diacetate (DCFH-DA) carcinogen treatment, the lesions exhibit white masses with a wrin\u00ad\nstaining, which can be oxidized to highly emissive 2\u2032,7\u2032-dichlorodihy\u00ad kled paper-like or verrucous appearance, indicating the successful\ndrofluorescein (DCF) by cellular ROS. A dose-dependent increase in DCF establishment of model to implement intervention. Upon accomplishing\nfluorescence is observed upon Ir1-mediated PDT treatment. Ir1 elevates intervention with certain treatment, the lesions in control group develop\nthe cellular ROS level to about 11.7-fold at 0.8 \u03bcM in the presence of into rough and hard surfaces accompanied by erosion, ulcer and\nlight (Fig. 2D). endogenous growth with unclear boundaries, while the malignancy in\n Moreover, cells subjected to Ir1-mediated PDT at different concen\u00ad combination treatment group turns out to be inhibited (Fig. 4B and S22).\ntrations were tested by western blotting for the two ER stress related Then, a histopathologic assessment of rat tongue samples was per\u00ad\nproteins, eukaryotic initiation factor 2 alpha (eIF2\u03b1) and C/EBP ho\u00ad formed based on the hematoxylin eosin (H&E) staining. In the combi\u00ad\nmologous protein (CHOP) [41,42]. Upon PDT treatment with Ir1, CHOP nation treatment group, only 1 (20%) case develops into mild invasion\nand phosphorylation of eIF2\u03b1 (p-eIF2\u03b1) are upregulated (Fig. 2E). These carcinoma, while in control group, 2 (40%) cases develop into moderate\n\n 5\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\n\n\nFig. 3. Ir1-mediated PDT triggers ICD and adaptively upregulates PD-L1 expression in vitro. (A-B) Cell surface CRT (A) and nuclear HMGB1 (B) expression levels in\nIr1-treated SCC1 cells measured by flow cytometry. SCC1 cells were incubated with Ir1 (0.2, 0.4 and 0.8 \u03bcM) for 24 h and irradiated with a 425 nm laser (20 mW\ncm\u2212 2, 15 min). (C) Extracellular ATP levels in Ir1-treated SCC1 cells measured by chemiluminescence assay. SCC1 cells were incubated with Ir1 for 24 h and\nirradiated with a 425 nm laser (20 mW cm\u2212 2, 15 min). (D) Correlation analysis between CRT and PD-L1 of OSCC patients in GSE65858 dataset. (E-F) The expression\nof PD-L1 in SCC1 cells treated with Ir1 (0.2, 0.4 and 0.8 \u03bcM; 24 h) in the presence of light (425 nm, 20 mW cm\u2212 2, 15 min) was measured by RT-qPCR (E) and western\nblotting (F). Quantitative analysis of western blotting of three independent repeats was performed by ImageJ software. In panel A-C and E-F, data were shown as the\nmean \u00b1 SD of three biological replicates; ns, no significance; *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001.\n\n\ninvasion carcinoma and 3 (60%) cases develop into severe invasion pathological alterations in major organs (heart, liver, spleen, lung and\ncarcinoma in their tongues (Fig. 4C and Table S4). Monotherapy with kidney) are found in all the treatment groups according to the histo\u00ad\neither Ir1-mediated PDT or PD-L1 inhibitor interrupts the malignant chemical analysis, indicating the low systemic toxicity of treatments\ntransformation process, while no significant inhibition is found in Ir1 (Fig. S24). Moreover, IHC staining shows that the expression of Ki67 is\ngroup without light irradiation (Fig. 4C and Table S4). Additionally, the significantly decreased in Ir1-medidated PDT and combination treat\u00ad\ncombination treatment group possesses the strongest inhibition effect ment mice, exerting a strong inhibition on tumor cell proliferation.\nwith the mean H&E score of 4, which is significantly lower than that in Notability, the PD-L1 expression is significantly upregulated in Ir1-\nthe control group (H&E score = 7.6; p < 0.001; Fig. 4D). medidated PDT group, which is consistent with the in vitro study, further\n Immunohistochemistry (IHC) results show that Ir1-mediated PDT in proving the feasibility of combination therapy. Encouragingly, in the\ncombination with PD-L1 inhibitor significantly decreases the positive combination treatment group, Ir1-mediated high PD-L1 expression is\nrates of Ki67. Meanwhile, the number of PD-L1+ cells is significantly reversed by the PD-L1 inhibitor to attenuate the immunosuppression\nincreased in the Ir1-mediated PDT group, while the immunosuppression (Fig. 5E). Taken together, these results indicate that Ir1-medidated PDT\nstatus is attenuated by PD-L1 inhibitor treatment (Fig. 4E). Taken plus PD-L1 inhibitor has the strongest tumor suppressive effect and re\u00ad\ntogether, these results indicate that the Ir1-mediated PDT exhibits sig\u00ad lieves the immunosuppressive TME in vivo.\nnificant carcinogenesis inhibition effects and synergizes with PD-L1\ntherapy in 4NQO induced rat model. 2.7. Ir1-medidated PDT combined with PD-L1 inhibitor synergistically\n augments antitumor immune responses\n2.6. Ir1-mediated PDT enhances the antitumor efficacy in combination\nwith PD-L1 inhibitor in vivo In order to investigate the potential immune mechanisms related to\n the favorable in vivo performance of combination treatment, a series of\n The antitumor efficacy was further evaluated in C57BL/6 mice immune studies were performed. CRT serves as an important \u201ceat me\u201d\nbearing SCC7 tumors (Fig. 5A). Both Ir1-medidated PDT and PD-L1 signal, which could help to promote tumor-specific antigen recognition\ninhibitor show a remarkable inhibition on tumor growth, and the and presentation and induce DCs maturation [51]. Compared with the\ncombination of the two modalities more significantly achieves the control group, the proportion of CRT+ tumor cells increases by about 2-\nregression of tumors (Fig. 5B). Meanwhile, no significant weight change fold in the Ir1-mediated PDT and combination treatment groups, veri\u00ad\nis found during treatment process, suggesting the relative safety for fying that Ir1-mediated PDT triggers ICD (Fig. 6A).\nadministration (Fig. S23). Subsequently, the tumor tissues from each To further determine if Ir1-mediated ICD alters the phenotypic and\ngroup were harvested. The average tumor weight of mice treated with functional maturation of DCs, the major histocompatibility class II\nsaline, Ir1 + light, PD-L1 inhibitor, and combination treatment is 0.46 g, (MHC-II) and costimulatory molecule CD80/CD86 on the surface of DCs\n0.19 g, 0.19 g, and 0.10 g respectively, indicating Ir1-mediated PDT plus were analyzed by flow cytometry. As shown in Fig. 6B and 6C, the\nPD-L1 inhibitor possesses the best antitumor effect (Fig. 5C and D). combination of PDT with PD-L1 inhibitor significantly upregulates the\n To further validate the therapeutic effects, H&E and IHC staining contents of MHC II+ and CD80+CD86+ DCs, which is superior to mon\u00ad\nwere performed on tumor tissue slices. In the combination treatment otherapy with either ICD induction or PD-L1 inhibition.\ngroup, H&E staining shows severe necrosis with noticeable vacuoliza\u00ad Mature DCs can present antigens to T cells, thereby activating T cells\ntion, massive nucleus absence and conspicuous karyopyknosis, revealing in TME to elicit adaptive immune responses [52,53]. Compared with the\nthe efficient antitumor killing effects (Fig. 5E). No serious structural or control and monotherapy groups, the combination treatment increases a\n\n 6\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\n\n\nFig. 4. Ir1-mediated PDT in combination with PD-L1 inhibitor inhibits carcinogenesis in 4NQO induced rat model. (A) Schematic overview of the 4NQO model\nexperimental design. (B) Representative gross observation and H&E images of the rat tongues in different groups at the endpoint. Scale bars: 5 mm for gross\nobservation, 400 \u00b5m for 5 \u00d7 magnification and 200 \u00b5m for 10 \u00d7 magnification. (C) Quantification of the histological degree of moderate dysplasia, severe dysplasia\nand carcinoma in situ, and invasive carcinoma in the six groups. (D) H&E scores of the histopathologic diagnoses in the six groups. (E) Representative IHC staining of\nKi67 and PD-L1. Scale bars: 50 \u00b5m. In panel D, data were shown as the mean \u00b1 SD. **p < 0.01 and ***p < 0.001.\n\n\nhigh level of tumor-specific CD4+ and CD8+ T cell infiltration, indi\u00ad enzyme-linked immunosorbent assay (ELISA). Consistent with above\ncating Ir1-mediated PDT and PD-L1 inhibitor treatment act synergisti\u00ad findings, the amount of TNF-\u03b1 and IFN-\u03b3 in tumors also appears to be the\ncally to potentiate anti-tumor adaptive immunity (Fig. 6D and E). It is highest in the combination therapy group for the activation of antitumor\nalso noteworthy that the PDT-induced increase of PD-1 expression on immunity (Fig. 6G). Meanwhile, immunosuppressive inflammatory\nCD8+ T cells is reversed by the PD-L1 inhibition (Fig. 6F). cytokine IL-6 is remarkably downregulated after combination treatment\n Subsequently, cytokines including tumor necrosis factor-\u03b1 (TNF-\u03b1), as compared to control group (Fig. 6G). TNF-\u03b1 and IFN-\u03b3 are key regu\u00ad\ninterferon-\u03b3 (IFN-\u03b3) and interleukin-6 (IL-6) in tumors were analyzed by lators for killing tumor and boosting antitumor immune response in the\n\n 7\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\n\n\nFig. 5. Ir1-mediated PDT in combination with PD-L1 inhibitor exhibits potent antitumor effects in CDX model. (A) Timeline illustration of the SCC7 xenograft model\nestablishment and therapeutic process in C57BL/6 mice. (B) Tumor growth curves of mice with indicated treatments for 17 days. (C) Representative images of the\nresected tumors at the end of the treatment. (D) The tumor weight at the end of the treatment. (E) H&E and IHC staining for Ki67 and PD-L1 of tumor sections after\nvarious treatments. Scale bar: 60 \u03bcm for H&E and 20 \u03bcm for IHC. In panel B and D, data were shown as the mean \u00b1 SD. *p < 0.05, **p < 0.01 and ****p < 0.0001.\n\n\nTME [54,55]. We find patients with higher expression of TNF-\u03b1 and IFN- the secretion of multiple antitumor cytokines and improves the response\n\u03b3 have longer overall survival than those with low expression in TCGA rate of PD-L1 inhibitor, which transforms \u201ccold tumor\u201d into \u201chot tumor\u201d\ndataset (Fig. 6H). IL\u20136 signaling acts to drive the proliferation, inva\u00ad for synergetic immunotherapy.\nsiveness and metastasis of tumor cells, and prevents T cell activation to\nsuppresses the antitumor immune response [56]. High expression of IL-6 3. Conclusion\nis also associated with a poor clinical prognosis in GSE4163 dataset\n(Fig. 6H). Besides, the correlation between CRT and resting DCs was In this study, we designed two new iridium(III) photosensitizers\nfurther analyzed in TCGA dataset. The result reveals that CRT is incorporating a ligand targeting ER by interacting with phospholipids\nsignificantly negatively correlated with resting DCs in tumor tissues, and proteins. Ir1 can generate ROS through both type I/II PDT pathways\nsuggesting the resting DCs have been activated with the increase of CRT to elicit ER stress in OSCC tumor cells upon irradiation. Interestingly,\n(Fig. S25). These results collectively show that the combination of Ir1- PDT treatment generates ICD leading to the release of DAMPs, which\nmediated PDT with PD-L1 blockade facilitates the maturation of DCs, promotes the upregulation of PD-L1 expression, yielding a basis on the\nenhances the recruitment and activation of antitumor T cells, promotes synergistic therapy. We prove that Ir1-mediated PDT induces the\n\n 8\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\n\n\nFig. 6. Ir1-mediated PDT enhances the immunogenicity and sensitizes tumors to PD-L1 inhibitor for potent anticancer immunity in CDX model. (A) Representative\nflow cytometry dot plots and statistical analysis of CRT expression (CRT+ cells gated on CD45\u2212 ) on tumor cell surface after various treatments. (B-C) Representative\nflow cytometry dot plots and statistical analysis of activated DCs (MHC II+ cells gated on CD45+CD11c+; B) and mature DCs (CD80+CD86+ cells gated on\nCD45+CD11c+; C) in tumors. (D-E) Representative flow cytometry dot plots and statistical analysis of CD4+ T cells (CD4+ cells gated on CD45+CD3+; D) and CD8+ T\ncells (CD8+ cells gated on CD45+CD3+; E) infiltration in tumors after various treatments. (F) Representative flow cytometry dot plots and statistical analysis of PD-1+\nT cells (PD-1+ cells gated on CD45+CD3+CD8+) infiltration in tumors after various treatments. (G) Levels of TNF-\u03b1, IFN-\u03b3 and IL-6 in tumor tissues of different\ntreatment groups measured by ELISA. (H) Kaplan-Meier survival curves of overall survival based on OSCC patients with high- and low-expression of TNF-\u03b1, IFN-\u03b3 and\nIL-6 (TCGA and GSE41613). In panel A-G, data were shown as the mean \u00b1 SD. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001.\n\n\n\n 9\n\fJ.-Y. Zhou et al. Chemical Engineering Journal 474 (2023) 145516\n\n\nmaturation of DCs, promotes the infiltration and activation of T cells in [9] S. Sen, M. Won, M.S. Levine, Y. Noh, A.C. Sedgwick, J.S. 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Rev. 49 (22) (2020) 8113\u20138136.\n [20] N. Rufo, A.D. Garg, P. Agostinis, The unfolded protein response in immunogenic\nthe work reported in this paper.\n cell death and cancer immunotherapy, Trends Cancer 3 (9) (2017) 643\u2013658.\n [21] K. Xiong, F. Wei, Y. Chen, L. Ji, H. Chao, Recent progress in photodynamic\nData availability immunotherapy with metal-based photosensitizers, Small Methods 7 (5) (2022)\n e2201403.\n [22] Y.Y. Ling, W.J. Wang, L. Hao, X.W. Wu, J.H. Liang, H. Zhang, Z.W. Mao, C.P. Tan,\n Data will be made available on request. Self-amplifying iridium(III) photosensitizer for ferroptosis-mediated\n immunotherapy against transferrin receptor-overexpressing cancer, Small 18 (49)\n (2022) e2203659.\nAcknowledgements [23] L. Zhou, F. Wei, J. Xiang, H. Li, C. Li, P. Zhang, C. Liu, P. Gong, L. Cai, K.M. Wong,\n Enhancing the ROS generation ability of a rhodamine-decorated iridium(iii)\n Jia-Ying Zhou, Qing-Hua Shen and Xiao-Jing Hong contributed complex by ligand regulation for endoplasmic reticulum-targeted photodynamic\n therapy, Chem. Sci. 11 (44) (2020) 12212\u201312220.\nequally to this work. This study was supported by the Science and [24] L. Fournel, Z. Wu, N. Stadler, D. Damotte, F. Lococo, G. Boulle, E. Segal-\nTechnology Project of Guangzhou, China (Grant No. 202206080009) Bendirdjian, A. Bobbio, P. Icard, J. Tredaniel, M. Alifano, P. Forgez, Cisplatin\nand the National Natural Science Foundation of China (Nos. 22022707 increases PD-L1 expression and optimizes immune check-point blockade in non-\n small cell lung cancer, Cancer Lett. 464 (2019) 5\u201314.\nand 22177142). Scheme 1C was created with biorender.com.\n [25] L. Li, Y. Li, C.H. Yang, D.C. Radford, J. Wang, M. Janat-Amsbury, J. Kopecek,\n J. 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