Nanoparticle-mediated immunogenic cell death for cancer immunotherapy.

The field of cancer therapy is witnessing the emergence of immunotherapy, an innovative approach that activates the body own immune system to combat cancer. Immunogenic cell death (ICD) has emerged as a prominent research focus in the field of cancer immunotherapy, attracting significant attention in recent years. The activation of ICD can induce the release of damage-associated molecular patterns (DAMPs), such as calreticulin (CRT), adenosine triphosphate (ATP), high mobility group box protein 1 (HMGB1), and heat shock proteins (HSP). Subsequently, this process promotes the maturation of innate immune cells, including dendritic cells (DCs), thereby triggering a T cell-mediated anti-tumor immune response. The activation of the ICD ultimately leads to the development of long-lasting immune responses against tumors. Studies have demonstrated that partial therapeutic approaches, such as chemotherapy with doxorubicin, specific forms of radiotherapy, and phototherapy, can induce the generation of ICD. The main focus of this article is to discuss and review the therapeutic methods triggered by nanoparticles for ICD, while briefly outlining their anti-tumor mechanism. The objective is to provide a comprehensive reference for the widespread application of ICD.

Combining cisplatin with Pinellia pedatisecta Schott lipid-soluble extract induces tumor immunogenic cell death in cervical cancer.

BACKGROUND: Pinellia pedatisecta Schott extract (PE) is extracted from Pinellia pedatisecta Schott (PPS), a traditional Chinese medicinal plant with the potential for direct anticancer effects or eliciting an anti-tumor response by activating the immune system. PURPOSE: To explore PE's ability and mechanism to reconstruct cisplatin's immunogenicity. METHODS: Cervical cancer cells were treated with cisplatin (CDDP) and/or PE. The exposure of calreticulin (CRT) on cell membrane was investigated by flow cytometry. The extracellular of ATP and HMGB1 was investigated by Western blot analysis, immunofluorescence and ELISA assay. Changes in immune profiles were using flow cytometry in vaccination and anti-tumor assays in vivo. Lastly, the mechanism of PE influenced the ROS/ERS pathway was examined by ROS assay kit, flow cytometry and Western blotting. RESULTS: PE treatment induced translocation of CRT from the endoplasmic reticulum to the cell membrane of tumor cells, concomitantly triggering immunogenic cell death (ICD). In terms of mechanisms, endoplasmic reticulum (ER) stress relievers could impede the ability of PE to induce immunogenicity. This indicates that PE is activated by ER stress, leading to subsequent induction of ICD. Upon analyzing RNA-seq data, it was observed that PE primarily induces programmed cell death in tumors by impeding upstream antioxidant mechanisms. Additionally, it transforms dying tumor cells into vaccines, activating a series of immune responses. CONCLUSIONS: This study observed for the first time that PE-induced CRT exposure on the membrane of cervical cancer cells compensates for the defect of nonimmunogenic cell death inducer CDDP thereby stimulating potent ICD. This ability restores the immunogenicity of CDDP through ER stress induced by the ROS signal. ROS played a role in PE's ability to induce ICD, leading to increased expression of ER stress-related proteins, including ATF3 and IRE-1α. PE exerted anti-cancer effects by increasing the ROS levels, and ROS/ERS signaling may be a potential avenue for cervical cancer treatment. Hence, the synergistic use of PE and CDDP holds potential for enhancing immunochemotherapy in cancer treatment.

Tannins in Phyllanthus emblica L. improves cisplatin efficacy in lung cancer cells by boosting endoplasmic reticulum stress to trigger immunogenic cell death.

BACKGROUND: Lung cancer is one of the deadliest cancers world-wide and immunotherapy has been considered as a promising therapeutic strategy. Previously, our study found that tannins in Phyllanthus emblica L. (PTF) could inhibit the growth of tumor by activating the immune response in liver cancer, and also exhibited a cytotoxicity on human lung cancer cells A549, H460, H1703 in vitro. OBJECTIVE: To explore whether PTF inhibited the growth of lung cancer through its immune-regulating function and to clarify underlying mechanisms. METHODS: The induction of immunogenic cell death (ICD) were characterized by calreticulin exposure, extracellular ATP secretion, and High Mobility Group Box 1(HMGB1) release both in vivo using LLC-derived xenograft tumor model and in vitro using both mouse LLC and human A549 cancer cells. RESULTS: PTF inhibited lung cancer cells growth and tumorigenesis in vivo/vitro and promoted anti-tumor immune responses. We further found that PTF could induce ICD, which then activated Type I interferon responses and CXCL9/10-mediated chemotaxis. Mechanistically, PTF induced the formation of intracellular protein aggregates and following activation of PERK/ATF4/CHOP-dependent endoplasmic reticulum stress-related ICD. Moreover, PTF improved the antitumor efficacy of cisplatin by inducing ICD both in vitro and in vivo. Finally, we screened out 5 components from PTF, including gallocatechin, gallic acid, methyl gallate, ethyl gallate and ellagic acid, which could induce ICD in vitro and might be considered as the potential antitumor pharmacodynamic substances. CONCLUSION: In conclusion, PTF inhibits the growth of lung cancer by triggering ICD and remodeling the tumor microenvironment, suggesting that PTF may have promising prospects as an adjacent immunotherapy for cancers.

Nanoplatform-enhanced photodynamic therapy for the induction of immunogenic cell death.

As an efficient, non-invasive, low-side-effect, and highly selective cancer therapy, photodynamic therapy (PDT) is used to treat various malignant tumors. However, the inefficiency of dealing with deep tumors and metastatic lesions highly limits the use of PDT. Immunogenic cell death (ICD) is a particular form of tumor cell death that could elicit a tumor-special immune response, leading to a systemic anti-tumor effect and providing therapeutic benefits for metastatic lesions. In this regard, it is crucial to enhance the ability of PDT to induce ICD. Luckily, advanced nanotechnology created many promising ways to improve the immunogenicity of PDT and achieve photoimmunotherapy. This review summarizes the emerging strategies for triggering immunogenic cell death via nanoplatform-enhanced PDT, with particular emphasis on their advantages in photoimmunotherapy. We highlight the nanoplatforms classified according to the basic principles of photodynamic therapy and immunogenic cell death, which provides a valuable reference for the design of nanoplatform for photoimmunotherapy. In addition, we also discuss the current situation and prospect of nano-based photoimmunotherapy in clinical studies.

Biomimetic Prussian blue nanocomplexes for chemo-photothermal treatment of triple-negative breast cancer by enhancing ICD.

Drug-induced immunogenic cell death (ICD) can efficiently inhibit tumor growth and recurrence through the release of tumor-associated antigens which activate both local and systemic immune responses. Pyroptosis has emerged as an effective means for inducing ICD; however, the development of novel pyroptosis inducers to specifically target tumor cells remains a pressing requirement. Herein, we report that Cinobufagin (CS-1), a main ingredient of Chansu, can effectively induce pyroptosis of triple-negative breast cancer (TNBC) cells, making it a potential therapeutic agent for this kind of tumor. However, the application of CS-1 in vivo is extremely limited by the high dosage/long-term usage and non-selectivity caused by systemic toxicity. To address these drawbacks, we developed a new nanomedicine by loading CS-1 into Prussian blue nanoparticles (PB NPs). The nanomedicine can release CS-1 in a photothermal-controlled manner inherited in PB NPs. Furthermore, hybrid membrane (HM) camouflage was adopted to improve the immune escape and tumor-targeting ability of this nanomedicine, as well. In vitro assays demonstrated that the chemo-photothermal combination treatment produced high-level ICD, ultimately fostering the maturation of dendritic cells (DCs). In vivo anti-tumor assessments further indicated that this strategy not only efficiently inhibited primary growth of MDA-MB-231 cells and 4T1 cells-bearing models but also efficiently attenuated distant tumor growth in 4T1 xenograft model. This was mechanistically achieved throuh the promotion of DCs maturation, infiltration of cytotoxic T lymphocyte into the tumor, and the inhibition of Treg cells. In summary, this work provides a novel strategy for efficient TNBC therapy by using nanomaterials-based multimodal nanomedicine through rational design.

Hyperthermia inhibits cellular function and induces immunogenic cell death in renal cell carcinoma.

BACKGROUND: In recent years, hyperthermia has been widely applied as a novel strategy for cancer treatment due to its multiple antitumour effects. In particular, the potential influences of hyperthermia on the tumour immune microenvironment may improve the efficacy of immunotherapies. However, the effect of hyperthermia on renal cell carcinoma (RCC) has not been well characterized until now. METHODS: In the present study, we primarily evaluated the effects of hyperthermia on cellular function via cellular proliferation, migration, invasion and apoptosis assays. In addition, the influence of hyperthermia on the immunogenicity of RCC cells was analysed using flow cytometry analysis, enzyme-linked immunosorbent assays, and immunofluorescent (IF) staining. RESULTS: Our results demonstrate that hyperthermia significantly inhibits RCC cell proliferation, migration, and invasion and promotes cell apoptosis. In addition, we verified that hyperthermia improves the immunogenicity of RCC cells by inducing immunogenic cell death. CONCLUSION: Our findings suggest that hyperthermia is a promising therapeutic strategy for RCC.

Dual Stimuli-Responsive Micelles for Imaging-Guided Mitochondrion-Targeted Photothermal/Photodynamic/Chemo Combination Therapy-Induced Immunogenic Cell Death.

Introduction: As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies. Methods: In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core. Results: In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities. Conclusion: In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.

Topological Regulating Bismuth Nano-Semiconductor for Immunogenic Cell Death-Mediated Sonocatalytic Hyperthermia Therapy.

Immunogenic cell death (ICD) can activate the body's immune system via dead cell antigens to achieve immunotherapy. Currently, small molecule drugs have been used for ICD treatment in clinical, however, how to precisely control the induced ICD while treating tumors is of great significance for improving therapeutic efficacy. Based on this, a sono/light dual response strategy to tumor therapy and activation of ICD is proposed. A topological synthesis method is used to obtain sulfur-doped bismuth oxide Bi2 O3-x Sx (BS) using BiF3 (BF) as a template through reduction and a morphology-controllable bismuth-based nano-semiconductor with a narrow bandgap is constructed. Under the stimulation of ultrasound, BS can produce reactive oxygen species (ROS) through the sonocatalytic process, which cooperates with BS to consume glutathione and enhance cellular oxidative damage, further inducing ICD. Due to the introduction of sulfur in the reduction reaction, BS can achieve photothermal conversion under light, and combine with ROS to treat tumors. Further, with the assistance of ivermectin (IVM) to form composite (BSM), combined with sono/light dual strategy, ICD is promoted and DCs maturation is accelerated. The proposed ICD-mediated hyperthermia/sonocatalytic therapy strategy will pay the way for synergetic enhancement of tumor treatment efficacy and provide a feasible idea for controllable induction of ICD.

Multifunctional Nanoplatform-Mediated Chemo-Photothermal Therapy Combines Immunogenic Cell Death with Checkpoint Blockade to Combat Triple-Negative Breast Cancer and Distant Metastasis.

Background: Breast cancer has become the most common cancer in women. Compare with other subtypes of breast cancer, triple-negative breast cancer (TNBC) is more likely to relapse and metastasize. Highly effective therapeutic strategies are desperately needed to be explored. In this study, a multifunctional nanoplatform is expected to mediate chemo-photothermal therapy, which can combine immunogenic cell death with checkpoint blockade to combat TNBC and distant metastasis. Methods: Poly (lactic acid-glycolic acid)-Poly (ethylene glycol) (PLGA-PEG) nanoparticles (NPs), a type of polymeric NPs, loaded with IR780, a near-infrared (NIR) dye, and doxorubicin (DOX) as the chemotherapeutic drug, were assembled by an improved double emulsification method (designated as IDNPs). The characterization, intracellular uptake, biosafety, photoacoustic (PA) imaging performance, and biodistribution of IDNPs were studied. Chemo-photothermal therapeutic effect and immunogenic cell death (ICD) were evaluated both in vitro and in vivo. The potency of chemo-photothermal therapy-triggered ICD in combination with anti-PD-1 immune checkpoint blockade (ICB) immunotherapy in eliciting immune response and treating distant tumors was further investigated. Results: IR780 and DOX were successfully loaded into PLGA-PEG to form the IDNPs, with size of 243.87nm and Zeta potential of -6.25mV. The encapsulation efficiency of IR780 and DOX was 83.44% and 5.98%, respectively. IDNPs demonstrated remarkable on-site accumulation and PA imaging capability toward 4T1 TNBC models. Chemo-photothermal therapy demonstrated satisfactory therapeutic effects both in vitro and in vivo, and triggered ICD efficiently. ICD, in combination with anti-PD-1, provoked a systemic antitumor immune response against distant tumors. Conclusion: Multifunctional IDNPs were successfully synthesized to mediate chemo-photothermal therapy, which combines immunogenic cell death with checkpoint blockade to combat TNBC and distant metastasis, showing great promise preclinically and clinically.

Reinforcing the immunogenic cell death to enhance cancer immunotherapy efficacy.

Immunogenic cell death (ICD) has been a revolutionary modality in cancer treatment since it kills primary tumors and prevents recurrent malignancy simultaneously. ICD represents a particular form of cancer cell death accompanied by production of damage-associated molecular patterns (DAMPs) that can be recognized by pattern recognition receptors (PRRs), which enhances infiltration of effector T cells and potentiates antitumor immune responses. Various treatment methods can elicit ICD involving chemo- and radio-therapy, phototherapy and nanotechnology to efficiently convert dead cancer cells into vaccines and trigger the antigen-specific immune responses. Nevertheless, the efficacy of ICD-induced therapies is restrained due to low accumulation in the tumor sites and damage of normal tissues. Thus, researchers have been devoted to overcoming these problems with novel materials and strategies. In this review, current knowledge on different ICD modalities, various ICD inducers, development and application of novel ICD-inducing strategies are summarized. Moreover, the prospects and challenges are briefly outlined to provide reference for future design of novel immunotherapy based on ICD effect.

Marsdenia tenacissima extract induces endoplasmic reticulum stress-associated immunogenic cell death in non-small cell lung cancer cells through targeting AXL.

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia Tenacissima (Roxb.) Wight et Arn. is a traditional Chinese medicine. Its standardized extract (MTE), with the trade name Xiao-Ai-Ping injection, is widely used for cancer treatment. The pharmacological effects of MTE-inducing cancer cell death have been primarily explored. However, whether MTE triggers tumor endoplasmic reticulum stress (ERS)-associated immunogenic cell death (ICD) is unknown. AIM OF THE STUDY: To determine the potential role of endoplasmic reticulum stress in the anti-cancer effects of MTE, and uncover the possible mechanisms of endoplasmic reticulum stress-associated immunogenic cell death induced by MTE. MATERIAL AND METHODS: The anti-tumor effects of MTE on non-small cell lung cancer (NSCLC) were examined through CCK-8 and wound healing assay. Network pharmacology analysis and RNA-sequencing (RNA seq) were performed to confirm the biological changes of NSCLCs after MTE treatment. Western blot, qRT-PCR, reactive oxygen species (ROS) assay, and mitochondrial membrane potential (MMP) assay were used to explore the occurrence of endoplasmic reticulum stress. Immunogenic cell death-related markers were tested by ELISA and ATP release assay. Salubrinal was used to inhibit the endoplasmic reticulum stress response. SiRNA and bemcentinib (R428) were used to impede the function of AXL. AXL phosphorylation was regained by recombinant human Gas6 protein (rhGas6). The effects of MTE on endoplasmic reticulum stress and immunogenic cell death response were also proved in vivo. The AXL inhibiting compound in MTE was explored by molecular docking and confirmed by Western blot. RESULTS: MTE inhibited cell viability and migration of PC-9 and H1975 cells. Enrichment analysis identified that differential genes after MTE treatment were significantly enriched in endoplasmic reticulum stress-related biological processes. MTE decreased mitochondrial membrane potential (MMP) and increased ROS production. Meanwhile, endoplasmic reticulum stress-related proteins (ATF6, GRP-78, ATF4, XBP1s, and CHOP) and immunogenic cell death-related markers (ATP, HMGB1) were upregulated, and the AXL phosphorylation level was suppressed after MTE treatment. However, when salubrinal (an endoplasmic reticulum stress inhibitor) and MTE were co-treated cells, the inhibitory effects of MTE on PC-9 and H1975 cells were impaired. Importantly, inhibition of AXL expression or activity also promotes the expression of endoplasmic reticulum stress and immunogenic cell death-related markers. Mechanistically, MTE induced endoplasmic reticulum stress and immunogenic cell death by suppressing AXL activity, and these effects were attenuated when AXL activity recovered. Moreover, MTE significantly increased the expression of endoplasmic reticulum stress-related markers in LLC tumor-bearing mouse tumor tissues and plasma levels of ATP and HMGB1. Molecular docking illustrated that kaempferol has the strongest binding energy with AXL and suppresses AXL phosphorylation. CONCLUSION: MTE induces endoplasmic reticulum stress-associated immunogenic cell death in NSCLC cells. The anti-tumor effects of MTE are dependent upon endoplasmic reticulum stress. MTE triggers endoplasmic reticulum stress-associated immunogenic cell death by inhibiting AXL activity. Kaempferol is an active component that inhibits AXL activity in MTE. The present research revealed the role of AXL in regulating endoplasmic reticulum stress and enriched the anti-tumor mechanisms of MTE. Moreover, kaempferol may be considered a novel AXL inhibitor.

IL5RA as an immunogenic cell death-related predictor in progression and therapeutic response of multiple myeloma.

Previous studies have shown the potential of immunogenic cell death-related modalities in myeloma. The significance of IL5RA in myeloma and immunogenic cell death remains unknown. We analyzed IL5RA expression, the gene expression profile, and secretory protein genes related to IL5RA level using GEO data. Immunogenic cell death subgroup classification was performed using the ConsensusClusterPlus and pheatmap R package. Enrichment analyses were based on GO/KEGG analysis. After IL5RA-shRNA transfection in myeloma cells, cell proliferation, apoptosis, and drug sensitivity were detected. P < 0.05 was considered statistically significant. IL5RA was upregulated in myeloma and progressed smoldering myeloma. We observed enrichment in pathways such as the PI3K-Akt signaling pathway, and Natural killer cell mediated cytotoxicity in the high-IL5RA group. IL5RA was also closely associated with secretory protein genes such as CST6. We observed the enrichment of cellular apoptosis and hippo signaling pathway on differential genes in the immunogenic cell death cluster. Furthermore, IL5RA was associated with immune infiltration, immunogenic cell death-related genes, immune-checkpoint-related genes, and m6A in myeloma. In vitro and in vivo experiments showed the involvement of IL5RA in apoptosis, proliferation, and drug resistance of myeloma cells. IL5RA shows the potential to be an immunogenic cell death-related predictor for myeloma.

NIR-II-absorbing diimmonium polymer agent achieves excellent photothermal therapy with induction of tumor immunogenic cell death.

Photothermal therapy has shown great promise for cancer treatment and second near-infrared (NIR-II) -absorbing particles could further improve its precision and applicability due to its superior penetration depth and new imaging ability. Herein, high NIR-II-absorbing polymer particles were prepared by using soluble isobutyl-substituted diammonium borates (P-IDI). The P-IDI showed stronger absorption at 1000-1100 nm, which exhibited excellent photostability, strong photoacoustic imaging ability and high photothermal conversion efficiency (34.7%). The investigations in vitro and in vivo demonstrated that the excellent photothermal effect facilitated complete tumor ablation and also triggered immunogenic cell death in activation of the immune response. The high solubility and excellent photothermal conversion ability demonstrated that polymer IDI particles were promising theranostic agents for treatment of tumors with minor side effects.

Induction of immunogenic cell death effect of licoricidin in cervical cancer cells by enhancing endoplasmic reticulum stress-mediated high mobility group box 1 expression.

Licoricidin (LCD) is an activity compound of the roots of Glycyrrhiza uralensis, which has therapeutic efficacy, including anti-virus, anti-cancer, and enhanced immunity in Traditional Chinese Medicine. Herein, this study aimed to clarify the effect of LCD on cervical cancer cells. In the present study, we found that LCD significantly inhibited cell viability via inducing cell apoptosis and companies with cleaved-PARP protein expression and caspase-3/-9 activity. Cell viability was markedly reversed these effects by pan-caspase inhibitor Z-VAD-FMK treatment. Furthermore, we showed that LCD-induced ER (endoplasmic reticulum) stress triggers upregulating the protein level of GRP78 (Bip), CHOP, and IRE1α, and subsequently confirmed the mRNA level by quantitative real-time polymerase chain reaction. In addition, LCD exhibited the release of danger-associated molecular patterns from cervical cancer cells, such as the release of high-mobility group box 1 (HMGB1), secretion of ATP, and exposure of calreticulin (CRT) on the cell surface, which led to immunogenic cell death (ICD). These results provide a novel foundation that LCD induces ICD via triggering ER stress in human cervical cancer cells. LCD might be an ICD inducer of immunotherapy in progressive cervical cancer.

Biomaterials That Induce Immunogenic Cell Death.

The immune system takes part in most physiological and pathological processes of the body, including the occurrence and development of cancer. Immunotherapy provides a promising modality for inhibition and even the cure of cancer. During immunotherapy, the immunogenic cell death (ICD) of tumor cells induced by chemotherapy, radiotherapy, phototherapy, bioactive materials, and so forth, triggers a series of cellular responses by causing the release of tumor-associated antigens and damage-associated molecular patterns, which ultimately activate innate and adaptive immune responses. Among them, the ICD-induced biomaterials attract increasing conditions as a benefit of biosafety and multifunctional modifications. This Review summarizes the research progress in biomaterials for inducing ICD via triggering endoplasmic reticulum oxidative stress, mitochondrial dysfunction, and cell membrane rupture and discusses the application prospects of ICD-inducing biomaterials in clinical practice for cancer immunotherapy.

Pre-Induced ICD Membrane-Coated Carrier-Free Nanoparticles for the Personalized Lung Cancer Immunotherapy.

Immunotherapy is a required adjuvant method in lung cancer therapy clinically. The single immune adjuvant failed to show the expected clinical therapeutic efficacy due to its rapid drug metabolism and inability to accumulate in the tumor site efficiently. Immunogenic cell death (ICD) is a new anti-tumor strategy combined with immune adjuvants. It can provide tumor-associated antigens, activate dendritic cells, and attract lymphoid T cells into the tumor microenvironment. Here doxorubicin-induced tumor membrane-coated iron (II)-cytosine-phosphate-guanine nanoparticles (DM@NPs) are shown for efficient co-delivery of tumor-associated antigens and adjuvant. Higher expression of ICD-related membrane proteins on the surface of the DM@NPs leads to the enhanced uptake of DM@NPs by dendritic cells (DCs), thereby promoting the DCs maturation and pro-inflammatory cytokines release. DM@NPs can remarkably increase the T cell infiltrations, remodel the tumor immune microenvironment and inhibit tumor progression in vivo. These findings reveal that pre-induced ICD tumor cell membrane-encapsulated nanoparticles can enhance immunotherapy responses and provide an effective biomimetic nanomaterial-based therapeutic strategy for lung cancer.

Cancer Immunotherapy Elicited by Immunogenic Cell Death Based on Smart Nanomaterials.

Cancer immunotherapy has been a revolutionary cancer treatment modality because it can not only eliminate primary tumors but also prevent metastases and recurrent tumors. Immunogenic cell death (ICD) induced by various treatment modalities, including chemotherapy, phototherapy, and radiotherapy, converts dead cancer cells into therapeutic vaccines, eliciting a systemic antigen-specific antitumor. However, the outcome effect of cancer immunotherapy induced by ICD has been limited due to the low accumulation efficiency of ICD inducers in the tumor site and concomitant damage to normal tissues. The boom in smart nanomaterials is conducive to overcoming these hurdles owing to their virtues of good stability, targeted lesion site, high bioavailability, on-demand release, and good biocompatibility. Herein, the design of targeted nanomaterials, various ICD inducers, and the applications of nanomaterials responsive to different stimuli, including pH, enzymes, reactive oxygen species, or dual responses are summarized. Furthermore, the prospect and challenges are briefly outlined to provide reference and inspiration for designing novel smart nanomaterials for immunotherapy induced by ICD.

Ultra-small NIR-Responsive Nanotheranostic Agent for Targeted Photothermal Ablation Induced Damage-Associated Molecular Patterns (DAMPs) from Post-PTT of Tumor Cells Activate Immunogenic Cell Death.

Theranostic nanoparticles (TNPs) is an efficient avenue that culminates both diagnosis and therapy into cancer treatment. Herein, we have formulated a theranostic nanocomposite (NC) with CuS being the ultra-small core component. To ensure stability to the NC, PEI was added which is a vital anchoring group polymer, especially on sulfide surfaces, and adds quality by being a better stabilizer and reducing agent. Additionally, to add stability, specificity, and added photothermal efficiency to the fabricated NC. In addition, encapsulation of indocyanine green (ICG), an efficient NIR absorber, and Folic acid (FA) were conjugated systematically, characterized, and analyzed for photo-stability. The photothermal conversion efficiency of the novel NC (CuS-PEI-ICG-FA) was analyzed at 808 nm, where the NC efficiently converted light energy to heat energy. The NC was also tested for hemocompatibility to clarify and also determined biocompatibility. Surprisingly, damage-associated molecular patterns (DAMPs) from post-PTT of tumor cells activate immunogenic cell death (ICD) for tumor-specific immune responses. The deserving photothermal performance and photo-stability makes the NC an ideal platform for photoacoustic imaging (PAI). A superior contrast was observed for PAI in a concentration-dependent manner enhancing the level of penetration into tissues, thereby better imaging. On account of this study, the newly formulated NC could be utilized as a "nanotheranostic" designed for therapeutic and image diagnostic agent of cancer biomedical applications.

Rhythm Mild-Temperature Photothermal Therapy Enhancing Immunogenic Cell Death Response in Oral Squamous Cell Carcinoma.

The low antitumor efficiency and unexpected thermo-tolerance activation of mild-temperature photothermal therapy (mPTT) severely impede the therapeutic efficacy, thereby the implementation of reasonable mPTT procedure to improve antitumor efficiency is of great significance for clinical transformation. Herein, a rhythm mPTT with organic photothermal nanoparticles (PBDB-T NPs) is demonstrated, synergistically increasing tumor elimination and intense immunogenic cancer cell death (ICD) to elicit tumor-specific immune responses for tumor treatment. Specifically, PBDB-T NPs are characterized by favorable biocompatibility, excellent and controllable photothermal properties, exhibit the properties of noninvasive diagnostic imaging, and effective mPTT against oral squamous cell carcinoma (OSCC). Encouragingly, a temperature-dependent release of damage-associated molecular patterns (DAMPs) is discovered during the mPTT-induced ICD. Meanwhile, orchestrated rhythm mPTT referring to radiotherapy procedure amplifies and balances antitumor efficiency and abundant DAMPs generation to gain optimal immune activation within clinical-recommended hyperthermia temperature compared with conventional PTT. The in vitro and in vivo results show that the rhythm mPTT unites the killing effect and ICD induction, generating strong mPTT efficacy and active tumor-specific adaptive immune responses. The study offers a promising strategy and a new opportunity for the clinical application of mPTT.

Activating Nanomedicines with Electromagnetic Energy for Deep-Tissue Induction of Immunogenic Cell Death in Cancer Immunotherapy.

Immunotherapy is an attractive approach for cancer therapy, while its antitumor efficacy is still limited, especially for non-immunogenic tumors. Nanomedicines can be utilized to convert the non-immunogenic "cold" tumors to immunogenic "hot" tumors via inducing immunogenic cell death (ICD), thereby promoting the antitumor immune response. Some nanomedicines that can produce local heat and reactive oxygen species upon the stimulation of electromagnetic energy are the main candidates for inducing the ICD effect. However, their applications are often restricted due to the poor tissue penetration depths of electromagnetic energy, such as light. By contrast, ultrasound, X-ray, alternating magnetic field, and microwave show excellent tissue penetration depths and thereby can be used for sonodynamic therapy, radiotherapy, magnetic hyperthermia therapy, and microwave ablation therapy, all of which can effectively induce ICD. Herein, the combination of deep-tissue electromagnetic energy with nanomedicines for inducing ICD and cancer immunotherapy are summarized. In particular, the designs of nanomedicines to amplify ICD effect in the presence of deep-tissue electromagnetic energy and sensitize tumors to various immunotherapies will be discussed. At the end of this review, a brief conclusion and discussion of current challenges and further perspectives in this subfield are provided.