Metastasis and heterogeneity pose major challenges in cancer treatment. Although chemoimmunotherapy shows promising efficacy, its therapeutic impact is limited by off-target effects and differences in the delivery sites of chemotherapeutic drugs and immunosuppressants. In this study, an engineered platelets (Pts)-based nano-aircraft, Pts@DOX/HANGs@Gal, was constructed with an internally loaded chemotherapeutic drug, doxorubicin, and externally grafted reduction-responsive hyaluronidase-cross-linked nanospheroids loaded with the immunosuppressant galunisertib for precise tumor chemo-immunotherapy. The normal physiological features of host Pts, including their excellent targeting capability for both metastatic and orthotopic tumors, are not disturbed by functional nanosystems. The interaction between Pts@DOX/HANGs@Gal and tumors gives rise to Pts activation, achieving the continuous targeted delivery of DOX to tumors, inducing the transition from cold to hot tumors, and promoting the recruitment of immune cells. Simultaneously, the external nanospheres disintegrate from Pts@DOX/HANGs@Gal, releasing galunisertib and hyaluronidase into the extracellular matrix to relieve immune tolerance and open up a high-speed channel for the tumor infiltration of immune cells and deep tumor penetration of the nanosystem. Consequently, Pts@DOX/HANGs@Gal not only effectively reinforced the antitumor immune response through self-recognized tumor-targeting chemo-immunotherapy and graded drug delivery but also reduced tumor metastasis in vivo. This study presents promising Pt-based nanovesicles for precise cancer treatment.

In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy, offering a targeted approach that uses the tumor microenvironment (TME) to stimulate an immune response directly at the tumor site. This method minimizes systemic exposure while maintaining therapeutic efficacy and enhancing safety. Recent advances in nanotechnology have enabled new approaches to ISV by utilizing nanomaterials with unique properties, including enhanced permeability, retention, and controlled drug release. ISV employing nanomaterials can induce immunogenic cell death and reverse the immunosuppressive and hypoxic TME, thereby converting a "cold" tumor into a "hot" tumor and facilitating a more robust immune response. This review examines the mechanisms through which nanomaterials-based ISV enhances anti-tumor immunity, summarizes clinical applications of these strategies, and evaluates its capacity to serve as a neoadjuvant therapy for eliminating micrometastases in early-stage cancer patients. Challenges associated with the clinical translation of nanomaterials-based ISV, including nanomaterial metabolism, optimization of treatment protocols, and integration with other therapies such as radiotherapy, chemotherapy, and photothermal therapy, are also discussed. Advances in nanotechnology and immunotherapy continue to expand the possible applications of ISV, potentially leading to improved outcomes across a broad range of cancer types.

Sulforaphane (SFN) is a natural isothiocyanate compound with multiple bioactive effects, abundantly found in cruciferous vegetables. SFN and cadmium (Cd) were limited in their application as chemotherapeutic agents due to insufficient cellular uptake, low bioavailability, and high systemic toxicity, respectively. In this study, mPEG-PLGA nanoparticles were used as a carrier to load Cd-γ-PGA conjugates and SFN, enabling favorable drug release under acidic microenvironments with excellent pH responsiveness. The NP-Cd-SFN nanoparticles exhibited a particle size of 102.1 nm, a zeta potential of -14.48 mV, and a PDI value of 0.257. These characteristics contribute to the nanoparticles' prolonged circulation in the bloodstream and their ability to passively target tumors. Compared to the single-dose groups and the combined Cd + SFN group, the NP-Cd-SFN group significantly reduced the viability of HepG2 cells and increased their apoptosis rate by inducing mitochondrial oxidative stress and promoting cell apoptosis. Overall, the addition of SFN and the encapsulation of mPEG-PLGA enhanced the therapeutic effects of Cd on HepG2 cells.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most feared diseases worldwide owing to its poor prognosis, negligible therapeutic advances, and high mortality. Herein, multifunctional enzyme-responsive micelles for the controlled delivery of paclitaxel (PTX) were prepared to circumvent its current clinical challenges. Accordingly, two enzyme-responsive structural units composed of Vitamin D3 (VD3) conjugated with polyethylene glycol of different molecular weights (600 Da and 2000 Da) were synthesized and characterized using different analytical methods. By applying the solvent evaporation method, these bioactive structural units self-assembled into sub-100 nm VD3 micelles with minimal batch-to-batch variation, monomodal particle size distribution, and high encapsulation efficiency. The enzyme-triggered disassembly of PTX-loaded VD3 micelles was demonstrated by release studies in the presence of a high esterase content typically featured by PDAC cells. PTX-loaded VD3 micelles also exhibited prominent cell internalization and induced a considerable cytotoxic synergistic effect against human PDAC cells (BxPC-3 cells) in 2D and 3D cell culture models compared with free PTX. The PTX-loaded VD3 micelles were hemocompatible and stable after long-term storage in the presence of biorelevant media, and showed higher efficiency to inhibit the tumor growth compared to the approved clinical nanoformulation (Abraxane®) in an in ovo tumor model. The findings reported here indicate that VD3S-PEG micelles may have a promising role in PDAC therapy, since VD3 could act not only as a hydrophobic core of the micelles but also as a therapeutic agent that provides synergetic therapeutic effects with the encapsulated PTX.

The tumor microenvironment, characterized by hypoxia, supports the efficacy of anaerobic bacteria like attenuated S. typhimurium in cancer therapies. These bacteria target and penetrate deep tumor regions, significantly reducing tumor size but often lead to tumor regrowth due to limited long-term efficacy. To enhance the therapeutic impact, a novel biohybrid system, S@UIL, has been developed by coating S. typhimurium with a zirconium-based nanoscale metal-organic framework (UiO-66-NH2) loaded with indocyanine green (ICG) and luteolin (LUT). This system maintains the bacteria's tumor-targeting ability while increasing the penetration and therapeutic effectiveness through excessive autophagy and mild hyperthermia. In a subcutaneous colon cancer model, the integration of LUT and ICG promotes autophagic cell death and photothermal sensitization, leading to the release of damage-associated molecular patterns (DAMPs). These DAMPs activate immune responses through dendritic cells and T-cells, enhancing immunogenic cell death (ICD) and potentially reducing immune evasion by tumors. This single-administration approach also integrates multimodal imaging capabilities, providing a promising strategy for improved tumor ICD induction and cancer progression inhibition.

Induction of immunogenic cell death (ICD) in tumors can enhance antitumor immunity and modulate immunosuppression in the tumor microenvironment (TME).

In the current study, we investigated the effect of silibinin, a natural compound with anticancer activity, and its polymer-based nanoformulations on the induction of apoptosis and ICD in cancer cells.

Free and nanoparticulate silibinin were evaluated for their growth-inhibitory effects using an MTT assay. Annexin V/PI staining was used to analyze apoptosis. Calreticulin (CRT) expression was measured by flow cytometry. Western blotting was conducted to examine the levels of elf2α, which plays a role in the ICD pathway. The HSP90 and ATP levels were determined using specific detection kits.

Compared to the free drug, silibinin-loaded nanocarriers significantly increased the induction of apoptosis and ICD in B16F10 cells. ICD induction was characterized by significantly increased levels of ICD biomarkers, including CRT, HSP90, and ATP. We also observed an increased expression of p-elf-2α/ elf-2α in B16F10 cells treated with silibinin-loaded micelles compared to cells that received free silibinin.

Our findings showed that the encapsulation of silibinin in polymeric nanocarriers can potentiate the effects of this drug on the induction of apoptosis and ICD in B16F10 melanoma cells.

Pancreatic cancer (PC) is a malignancy of the gastrointestinal tract that is characterized by a poor prognosis. This study investigates the roles of immunogenic cell death (ICD) genes in the prognosis and progression of PC. Expression data for PC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, while ICD genes were sourced from published literature. We explored the expression patterns and identified two distinct clusters based on ICD genes. Kaplan-Meier analysis, differential expression analysis, tumor mutational burden analysis, and immune cell infiltration analysis were performed on these clusters. An ICD gene-based risk model was developed, categorizing samples from the TCGA and GEO datasets into low- and high-risk groups. Additionally, we investigated the expression levels of the genes included in the risk model within the TCGA cohort and our own samples. Finally, a loss-of-function assay was conducted to assess the role of MYD88 in PC. Two clusters of PC samples were identified, patients in the ICD-low cluster exhibited a higher degree of immune cell enrichment. The survival time of patients in the low-risk group was longer than that of those in the high-risk group. The genes included in the risk model (CASP1, MYD88, and PIK3CA) showed upregulated expression levels in tumor samples. Furthermore, the predictive accuracy of our risk model was validated using our own samples. Genetic inhibition of MYD88 led to significantly decreased proliferation and migration of PC cells in the loss-of-function assay. There were disparities in survival time and tumor immune microenvironment (TIME) between two ICD gene clusters. Additionally, we developed an ICD-related risk model that was validated as an independent prognostic indicator for patients with PC.

Current standard-of-care therapies have failed to improve the survival of patients with metastatic pancreatic cancer (PCA). Therefore, exploring novel therapeutic approaches for cancer targeting is of utmost need. During the past few years, many efforts have been made to develop conventional treatment strategies to reduce chemotherapy resistance. However, critical challenges have impeded current cancer management outcomes, and limited clinical responses have been achieved due to unfavorable off-target effects. Advances in nanotechnology-based gene and immune-modulator delivery systems have excellent advantages for improving the therapeutic efficacy of PCA and provide promising avenues for overcoming the immunosuppressive tumor microenvironment and enhancing patient treatment outcomes. This review article provides insight into the challenges, opportunities, and future perspectives of these novel emerging nanoparticles based on lipid, polymer, and inorganic metal carriers to modulate genes and immunotherapy paradigms for PCA anticancer activity.

Preventive cancer vaccines are highly effective in preventing viral infection-induced cancer, but advances in therapeutic cancer vaccines with a focus on eliminating cancer cells through immunotherapy are limited. To develop therapeutic cancer vaccines, the integration of optimal adjuvants is a potential strategy to enhance or complement existing therapeutic approaches. However, conventional adjuvants do not satisfy the criteria of clinical trials for therapeutic cancer vaccines. To improve the effects of adjuvants in therapeutic cancer vaccines, effective vaccination strategies must be formulated and novel adjuvants must be identified. This review offers an overview of the current advancements in therapeutic cancer vaccines and highlights in situ vaccination approaches that can be synergistically combined with other immunotherapies by harnessing the adjuvant effects. Additionally, the refinement of adjuvant systems using cutting-edge technologies and the elucidation of molecular mechanisms underlying immunogenic cell death to facilitate the development of innovative adjuvants have been discussed.

Pancreatic ductal adenocarcinoma (PDAC) has a survival rate of 12%, and multiple clinical trials testing anti-PD-1 therapies against PDAC have failed, suggesting a need for a novel therapeutic strategy. In this study, we evaluated the potential of milbemycin oxime (MBO), an antiparasitic compound, as an immunomodulatory agent in PDAC. Our results show that MBO inhibited the growth of multiple PDAC cell lines by inducing apoptosis. In vivo studies showed that the oral administration of 5 mg/kg MBO inhibited PDAC tumor growth in both subcutaneous and orthotopic models by 49% and 56%, respectively. Additionally, MBO treatment significantly increased the survival of tumor-bearing mice by 27 days as compared to the control group. Interestingly, tumors from MBO-treated mice had increased infiltration of CD8+ T cells. Notably, depletion of CD8+ T cells significantly reduced the anti-tumor efficacy of MBO in mice. Furthermore, MBO significantly augmented the efficacy of anti-PD-1 therapy, and the combination treatment resulted in a greater proportion of active cytotoxic T cells within the tumor microenvironment. MBO was safe and well tolerated in all our preclinical toxicological studies. Overall, our study provides a new direction for the use of MBO against PDAC and highlights the potential of repurposing MBO for enhancing anti-PD-1 immunotherapy.

Glioblastoma multiforme (GBM) is the most severe form of brain cancer and presents unique challenges to developing novel treatments due to its immunosuppressive milieu where receptors like programmed death ligand 1 (PD-L1) are frequently elevated to prevent an effective anti-tumor immune response. To potentially shift the GBM environment from being immunosuppressive to immune-enhancing, we engineered a novel nanovehicle from reduced graphene oxide quantum dot (rGOQD), which are loaded with the immunomodulatory drug resiquimod (R848) and conjugated with an anti-PD-L1 antibody (aPD-L1). The immunomodulatory rGOQD/R8/aPDL1 nanoparticles can actively target the PD-L1 on the surface of ALTS1C1 murine glioblastoma cells and release R848 to enhance the T-cell-driven anti-tumor response. From in vitro experiments, the PD-L1-mediated intracellular uptake and the rGOQD-induced photothermal response after irradiation with near-infrared laser light led to the death of cancer cells and the release of damage-associated molecular patterns (DAMPs). The combinational effect of R848 and released DAMPs synergistically produces antigens to activate dendritic cells, which can prime T lymphocytes to infiltrate the tumor in vivo. As a result, T cells effectively target and attack the PD-L1-suppressed glioma cells and foster a robust photothermal therapy elicited anti-tumor immune response from a syngeneic mouse model of GBM with subcutaneously implanted ALTS1C1 cells.

Cancer immunotherapy remains a significant challenge due to insufficient proliferation of immune cells and the sturdy immunosuppressive tumor microenvironment. Herein, we proposed the hypothesis of cuproptosis-lactate regulation to provoke cuproptosis and enhance anti-tumor immunity. For this purpose, copper-human serum albumin nanocomplex loaded gold nanocages with bacterial membrane coating (BAu-CuNCs) were developed. The targeted delivery and disassembly of BAu-CuNCs in tumor cells initiated a cascade of reactions. Under near infrared (NIR) laser irradiation, the release of copper-human serum albumin (Cu-HSA) was enhanced that reacted with intratumoral glutathione (GSH) via a disulfide exchange reaction to liberate Cu2+ ions and exert cuproptosis. Subsequently, the cuproptosis effect triggered immunogenic cell death (ICD) in tumor by the release of damage associated molecular patterns (DAMPs) to realize anti-tumor immunity via robust production of cytotoxic T cells (CD8+) and helper T cells (CD4+). Meanwhile, under NIR irradiation, gold nanocages (AuNCs) promoted excessive reactive oxygen species (ROS) generation that played a primary role in inhibiting glycolysis, reducing the lactate and ATP level. The combine action of lower lactate level, ATP reduction and GSH depletion further sensitized the tumor cells to cuproptosis. Also, the lower lactate production led to the significant blockage of immunosuppressive T regulatory cells (Tregs) and boosted the anti-tumor immunity. Additionally, the effective inhibition of breast cancer metastasis to the lungs enhanced the anti-tumor therapeutic impact of BAu-CuNCs + NIR treatment. Hence, BAu-CuNCs + NIR concurrently induced cuproptosis, ICD and hindered lactate production, leading to the inhibition of tumor growth, remodeling of the immunosuppressive tumor microenvironment and suppression of lung metastasis. Therefore, leveraging cuproptosis-lactate regulation, this approach presents a novel strategy for enhanced tumor immunotherapy.

The lysosome-targeting chimera (LYTAC) approach has shown promise for the targeted degradation of secreted and membrane proteins via lysosomes. However, there have been challenges in design, development, and targeting. Here, we have designed a genetically engineered transferrin receptor (TfR)-mediated lysosome-targeting chimera (TfR-LYTAC) that is efficiently internalized via TfR-mediate endocytosis and targets PD-L1 for lysosomal degradation in cultured cells but not in vivo due to short half-life and poor tumor targeting. A delivery platform was developed by fusing TfR-LYTAC to the surface of bacterial outer membrane vesicles (OMVs). The engineered OMV-LYTAC combines PD-1/PD-L1 pathway inhibition with LYTAC and immune activation by bacterial OMVs. OMV-LYTAC significantly reduced tumor growth in vivo. We have provided a modular and simple genetic strategy for lysosomal degradation as well as a delivery platform for in vivo tumor targeting. The study paves the way for the targeting and degradation of extracellular proteins using the TfR-LYTAC system.

Regulated cell death (RCD) is a form of cell death that can be regulated by numerous biomacromolecules. Accumulating evidence suggests that dysregulated expression and altered localization of related proteins in RCD promote the development of cancer. Targeting subroutines of RCD with pharmacological small-molecule compounds is becoming a promising therapeutic avenue for anti-tumor treatment, especially in hematological malignancies. Herein, we summarize the aberrant mechanisms of apoptosis, necroptosis, pyroptosis, PANoptosis, and ferroptosis in hematological malignancies. In particular, we focus on the relationship between cell death and tumorigenesis, anti-tumor immunotherapy, and drug resistance in hematological malignancies. Furthermore, we discuss the emerging therapeutic strategies targeting different RCD subroutines. This review aims to summarize the significance and potential mechanisms of RCD in hematological malignancies, along with the development and utilization of pertinent therapeutic strategies.

Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment (TME) leading to failure of immune response. Numerous therapeutic strategies including chemotherapy, radiotherapy, photodynamic, photothermal, magnetic, chemodynamic, sonodynamic and oncolytic therapy, have been developed to induce immunogenic cell death (ICD) of cancer cells and thereby elicit immunogenicity and boost the antitumor immune response. However, many challenges hamper the clinical application of ICD inducers resulting in modest immunogenic response. Here, we outline the current state of using nanomedicines for boosting ICD of cancer cells. Moreover, synergistic approaches used in combination with ICD inducing nanomedicines for remodeling the TME via targeting immune checkpoints, phagocytosis, macrophage polarization, tumor hypoxia, autophagy and stromal modulation to enhance immunogenicity of dying cancer cells were analyzed. We further highlight the emerging trends of using nanomaterials for triggering amplified ICD-mediated antitumor immune responses. Endoplasmic reticulum localized ICD, focused ultrasound hyperthermia, cell membrane camouflaged nanomedicines, amplified reactive oxygen species (ROS) generation, metallo-immunotherapy, ion modulators and engineered bacteria are among the most innovative approaches. Various challenges, merits and demerits of ICD inducer nanomedicines were also discussed with shedding light on the future role of this technology in improving the outcomes of cancer immunotherapy.

Until now, there has been a lack of effective strategies for cancer treatment. Immunotherapy has high potential in treating several cancers but its efficacy is limited as a monotherapy. Chemoimmunotherapy (CIT) holds promise to be widely used in cancer treatment. Therefore, identifying their involvement and potential synergy in CIT approaches is decisive. Nano-based drug delivery systems (NDDSs) are ideal delivery systems because they can simultaneously target immune cells and cancer cells, promoting drug accumulation, and reducing the toxicity of the drug. In this review, we first introduce five current immunotherapies, including immune checkpoint blocking (ICB), adoptive cell transfer therapy (ACT), cancer vaccines, oncolytic virus therapy (OVT) and cytokine therapy. Subsequently, the immunomodulatory effects of chemotherapy by inducing immunogenic cell death (ICD), promoting tumor killer cell infiltration, down-regulating immunosuppressive cells, and inhibiting immune checkpoints have been described. Finally, the NDDSs-mediated collaborative drug delivery systems have been introduced in detail, and the development of NDDSs-mediated CIT nanoparticles has been prospected.

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.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer resistant to current therapies, including oxaliplatin (Oxa). Growing evidence supports the ability of cancers to harness sphingolipid metabolism for survival. Sphingosine-1-phosphate (S1P) is an anti-apoptotic, pro-survival mediator that can influence cellular functions such as endoplasmic reticulum (ER) stress. We hypothesize that PDAC drives dysregulated sphingolipid metabolism and that S1P inhibition can enhance ER stress to improve therapeutic response to Oxa in PDAC.

RNA sequencing data of sphingolipid mediators from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx) datasets were analyzed. Murine and human PDAC cell lines were treated with small interfering RNA (siRNA) against sphingosine kinase-2 (SPHK2) or ABC294640 (ABC) and incubated with combinations of vehicle control or Oxa. In an orthotopic syngeneic KPC PDAC model, tumors were treated with either vehicle control, Oxa, ABC, or combination therapy.

RNA sequencing analysis revealed multiple significantly differentially expressed sphingolipid mediators (P < 0.05). In vitro, both siRNA knockdown of SPHK2 and ABC sensitized cells to Oxa therapy (P < 0.05), and induced eukaryotic initiation factor 2α (eIF2α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) phosphorylation, hallmarks of ER stress. In vitro therapy also increased extracellular high mobility group box 1 (HMGB1) release (P < 0.05), necessary for immunogenic cell death (ICD). In vivo combination therapy increased apoptotic markers as well as the intensity of HMGB1 staining compared to control (P < 0.05).

Our evidence suggests that sphingolipid metabolism is dysregulated in PDAC. Furthermore, S1P inhibition can sensitize PDAC to Oxa therapy through increasing ER stress and can potentiate ICD induction. This highlights a potential therapeutic target for chemosensitizing PDAC as well as an adjunct for future chemoimmunotherapy strategies.

Nanotechnology profoundly affects the advancement of medicine. Limitations in diagnosing and treating cancer and chronic diseases promote the growth of nanomedicine. However, there are very few analytical and descriptive studies regarding the trajectory of nanomedicine, key research powers, present research landscape, focal investigative points, and future outlooks. Herein, articles and reviews published in the Science Citation Index Expanded of Web of Science Core Collection from first January 2000 to 18th July 2023 are analyzed. Herein, a bibliometric visualization of publication trends, countries/regions, institutions, journals, research categories, themes, references, and keywords is produced and elaborated. Nanomedicine-related academic output is increasing since the COVID-19 pandemic, solidifying the uneven global distribution of research performance. While China leads in terms of publication quantity and has numerous highly productive institutions, the USA has advantages in academic impact, commercialization, and industrial value. Nanomedicine integrates with other disciplines, establishing interdisciplinary platforms, in which drug delivery and nanoparticles remain focal points. Current research focuses on integrating nanomedicine and cell ferroptosis induction in cancer immunotherapy. The keyword "burst testing" identifies promising research directions, including immunogenic cell death, chemodynamic therapy, tumor microenvironment, immunotherapy, and extracellular vesicles. The prospects, major challenges, and barriers to addressing these directions are discussed.

Inhibition of glutamine metabolism in tumor cells can cause metabolic compensation-mediated glycolysis enhancement and PD-L1 upregulation-induced immune evasion, significantly limiting the therapeutic efficacy of glutamine inhibitors. Here, inspired by the specific binding of receptor and ligand, a PD-L1-targeting metabolism and immune regulator (PMIR) are constructed by decorating the glutaminase inhibitor (BPTES)-loading zeolitic imidazolate framework (ZIF) with PD-L1-targeting peptides for regulating the metabolism within the tumor microenvironment (TME) to improve immunotherapy. At tumor sites, PMIR inhibits glutamine metabolism of tumor cells for elevating glutamine levels within the TME to improve the function of immune cells. Ingeniously, the accompanying PD-L1 upregulation on tumor cells causes self-amplifying accumulation of PMIR through PD-L1 targeting, while also blocking PD-L1, which has the effects of converting enemies into friends. Meanwhile, PMIR exactly offsets the compensatory glycolysis, while disrupting the redox homeostasis in tumor cells via the cooperation of components of the ZIF and BPTES. These together cause immunogenic cell death of tumor cells and relieve PD-L1-mediated immune evasion, further reshaping the immunosuppressive TME and evoking robust immune responses to effectively suppress bilateral tumor progression and metastasis. This work proposes a rational strategy to surmount the obstacles in glutamine inhibition for boosting existing clinical treatments.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide with a high degree of heterogeneity. Cuproptosis and immunogenic cell death (ICD) have been considered to be vital for tumor progression. However, current understanding of cuproptosis and immunogenic cell death in DLBCL is still very limited. We aim to explore a prognostic model combining cuproptosis and immunogenic cell death in DLBCL.

Pearson's correlation analysis was utilized to acquire lncRNAs associated with cuproptosis and immunogenic cell death. Prognostic biomarker identification and model construction involved the use of univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. We assessed the predictive capability of the risk model by conducting Kaplan-Meier analysis and time-dependent ROC analysis. The analysis and comparison of immune infiltration and drug sensitivity were conducted in this study. Moreover, RT-qPCR was employed to validate the expression of lncRNAs associated with cuproptosis and immunogenic cell death in DLBCL cell lines.

We identified 4 prognosis-related lncRNAs (ANKRD10-IT1, HOXB-AS1, LINC00520 and LINC01165) that were correlated with cuproptosis and immunogenic cell death. The model was verified to have a good and independent predictive ability in the prognostic prediction of DLBCL patients. Moreover, significant difference was observed in immune infiltration and drug sensitivity between high- and low-risk groups.

Our discoveries could enhance the comprehension of the role of cuproptosis and ICD in DLBCL, potentially offering novel viewpoints and knowledge for personalized and precise treatment of DLBCL individuals.

Cancer is a complex disease that, despite advances in treatment and the greater understanding of the tumor biology until today, continues to be a prevalent and lethal disease. Chemotherapy, radiotherapy, and surgery are the conventional treatments, which have increased the survival for cancer patients. However, the complexity of this disease together with the persistent problems due to tumor progression and recurrence, drug resistance, or side effects of therapy make it necessary to explore new strategies that address the challenges to obtain a positive response. One important point is that tumor cells can interact with the microenvironment, promoting proliferation, dissemination, and immune evasion. Therefore, immunotherapy has emerged as a novel therapy based on the modulation of the immune system for combating cancer, as reflected in the promising results both in preclinical studies and clinical trials obtained. In order to enhance the immune response, the combination of immunotherapy with nanoparticles has been conducted, improving the access of immune cells to the tumor, antigen presentation, as well as the induction of persistent immune responses. Therefore, nanomedicine holds an enormous potential to enhance the efficacy of cancer immunotherapy. Here, we review the most recent advances in specific molecular and cellular immunotherapy and in nano-immunotherapy against cancer in the light of the latest published preclinical studies and clinical trials.

Oncolytic virotherapy (OVT) is a promising form of cancer treatment that uses genetically engineered viruses to replicate within cancer cells and trigger anti-tumor immune response. In addition to killing cancer cells, oncolytic viruses can also remodel the tumor microenvironment and stimulate a long-term anti-tumor immune response. Despite achieving positive results in cellular and organismal studies, there are currently only a few approved oncolytic viruses for clinical use. Vaccinia virus (VACV) has emerged as a potential candidate due to its ability to infect a wide range of cancer cells. This review discusses the mechanisms, benefits, and clinical trials of oncolytic VACVs. The safety and efficacy of different viral backbones are explored, as well as the effects of oncolytic VACVs on the tumor microenvironment. The potential combination of oncolytic VACVs with immunotherapy or traditional therapies is also highlighted. The review concludes by addressing prospects and challenges in the field of oncolytic VACVs, with the aim of promoting further research and application in cancer therapy.

A strategy for designing cancer therapeutic nanovaccines based on immunogenic cell death (ICD)-inducing therapeutic modalities is particularly attractive for optimal therapeutic efficacy. In this work, a highly effective cancer therapeutic nanovaccine (denoted as MPL@ICC) based on immunogenic photodynamic therapy (PDT) was rationally designed and fabricated. MPL@ICC was composed of a nanovehicle of MnO2 modified with a host-guest complex using amino pillar[6]arene and lactose-pyridine, a prodrug of isoniazid (INH), and chlorine e6 (Ce6). The nanovaccine exhibited excellent biosafety, good targeting ability to hepatoma cells and enrichment at tumor sites. Most importantly, it could modulate the tumor microenvironment (TME) to facilitate the existence of Mn(iii) and Mn(iii)-mediated carbon-centered radical generation with INH released from the prodrug in situ to further strengthen ICD. This is the first report on Mn(iii)-mediated generation of carbon-centered radicals for successful anti-tumor immunotherapy using ICD, which provides a novel strategy for designing highly efficient cancer therapeutic nanovaccines.

The immune system assumes a pivotal role in the organism's capacity to discern and obliterate malignant cells. The immunogenicity of a cancer cell pertains to its proficiency in inciting an immunological response. The prowess of immunogenicity stands as a pivotal determinant in the triumph of formulating immunotherapeutic methodologies. Immunotherapeutic strategies include immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and on vaccines. Immunogenic cell death (ICD) epitomizes a form of cellular demise that incites an immune response against dying cells. ICD is characterized by the liberation of distinct specific molecules that activate the immune system, thereby leading to the identification and elimination of dying cells by immunocytes. One of the salient characteristics inherent to the ICD phenomenon resides in the vigorous liberation of adenosine triphosphate (ATP) by cellular entities dedicated to embarking upon the process of programmed cell death, yet refraining from complete apoptotic demise. ICD is initiated by a sequence of molecular events that occur during cell death. These occurrences encompass the unveiling or discharge of molecules such as calreticulin, high-mobility group box 1 (HMGB1), and adenosine triphosphate (ATP) from dying cells. These molecules act as "eat me" signals, which are recognized by immune cells, thereby prompting the engulfment and deterioration of expiring cells by phagocytes including various pathways such as Necroptosis, Apoptosis, and pyroptosis. Here, we review our current understanding of the pathophysiological importance of the immune responses against dying cells and the mechanisms underlying their activation. Overall, the ICD represents an important mechanism by which the immune system recognizes and eliminates dying cells, including cancer cells. Understanding the molecular events that underlie ICD bears the potential to engender innovative cancer therapeutics that harness the power of the immune system to combat cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease that responds poorly to single-drug immunotherapy with PD-L1 (CD274) inhibitors. Here, we prepared mesoporous nanomaterials Cu2MoS4 (CMS)/PEG loaded with PD-L1 inhibitor BMS-1 and CXCR4 inhibitor Plerixafor to form the nanodrug CMS/PEG-B-P. In vitro experiments, CMS/PEG-B-P have a more substantial inhibitory effect on the expression of PD-L1 and CXCR4 as well as to promote the apoptosis of pancreatic cancer cells KPC and suppressed KPC cell proliferation were detected by flow cytometry, qPCR and Western blotting (WB). Promotes the release of the cytotoxic substance reactive oxygen species (ROS) and the production of the immunogenic cell death (ICD) marker calreticulin (CRT) in KPC cells. CMS/PEG-B-P was also detected to have a certain activating effect on mouse immune cells, dendritic cells (mDC) and macrophage RAW264.7. Subcutaneous tumorigenicity experiments in C57BL/6 mice verified that CMS/PEG-B-P had an inhibitory effect on the growth of tumors and remodeling of the tumor immune microenvironment, including infiltration of CD4+ and CD8+ T cells and polarization of macrophages, as well as reduction of immunosuppressive cells. Meanwhile, CMS/PEG-B-P was found to have different effects on the release of cytokines in the tumor immune microenvironment, including The levels of immunostimulatory cytokines INF-γ and IL-12 are increased and the levels of immunosuppressive cytokines IL-6, IL-10 and IFN-α are decreased. In conclusion, nanomaterial-loaded immune checkpoint inhibitor therapies can enhance the immune response and reduce side effects, a combination that shows great potential as a new immunotherapeutic approach. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease that has a low response to single-drug immunotherapy with PD-L1 (CD274) inhibitors. We preared PEG-modified mesoporous nanomaterials Cu2MoS4 (CMS) loaded with PD-L1 inhibitor BMS-1 and CXCR4 inhibitor Plerixafor to form the nanodrug CMS/PEG-B-P. Our study demonstrated that Nanomaterial-loaded immune checkpoint inhibitor therapies can enhance the immune response and reduce side effects, a combination that shows great potential as a new immunotherapeutic approach.

Immunotherapy has attracted widespread attention in cancer treatment and has achieved considerable success in the clinical treatment of some tumors, but it has a low response rate in most tumors. To achieve sufficient activation of the immune response, significant efforts using nanotechnology have been made to enhance cancer immune response. In recent years, the induction of various regulated cell death (RCD) has emerged as a potential antitumor immuno-strategy, including processes related to apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and cuproptosis. In particular, damage-associated molecular patterns (DAMPs) released from the damaged membrane of dying cells act as in situ adjuvants to trigger antigen-specific immune responses by the exposure of an increased antigenicity. Thus, RCD-based immunotherapy offers a new approach for enhancing cancer treatment efficacy. Furthermore, incorporation with multimodal auxiliary therapies in cell death-based immunotherapy can trigger stronger immune responses, resulting in more efficient therapeutic outcome. This review discusses different RCD modalities and summarizes recent nanotechnology-mediated RCDs in cancer immunotherapy.

Photodynamic therapy (PDT) has emerged as an efficient approach for non-invasive cancer treatment. However, organic small-molecule photosensitizers are often associated with defects in hydrophobicity, poor photostability, and aggregation-caused quenching, which limit their application. Usually, the carrier-assisted drug delivery system is a common strategy to solve the above obstacles, but additional carrier material could increase the risk of potential biological toxicity. The carrier-free drug delivery system with easy preparation and high drug-loading capability is proposed subsequently as a potential strategy to develop the clinical use of hydrophobic drugs. Herein, we rationally designed three IR780-based carrier-free nanosystems formed by carbon/disulfide/diselenide bond conjugated IR780-based homodimers. The IR780-based homodimers could self-assemble to form nanoparticles (DC-NP, DS-NP, DSe-NP) and exhibited higher reactive oxygen species generation capability and photostability than free IR780, in which DSe-NP with 808 nm laser irradiation performed best and resulted in the strongest cytotoxicity to 4T1 cells. Meanwhile, the glutathione consumption ability of DSe-NP boosted its PDT effect and then induced excessive oxidative stress of 4T1 cells, increasing antitumor efficacy by enhancing immunogenic cell death further. In tumor-bearing mice, DSe-NP displayed obvious tumor site accumulation, which obviously inhibited tumor growth and metastasis, and enhanced the immunological effect by effectively inducing dendritic cells to mature and activating T lymphocytes and natural killer cells. In summary, our study presented an IR780-based carrier-free nanodelivery system for a combination of PDT and immunity therapy and established expanding the application of organic small-molecule photosensitizers by an approach of carrier-free drug delivery system.

Pancreatic cancer remains a formidable challenge due to limited treatment options and its aggressive nature. In recent years, the naturally occurring anticancer compound juglone has emerged as a potential therapeutic candidate, showing promising results in inhibiting tumor growth and inducing cancer cell apoptosis. However, concerns over its toxicity have hampered juglone's clinical application. To address this issue, we have explored the use of polymeric micelles as a delivery system for juglone in pancreatic cancer treatment. These micelles, formulated using Poloxamer 407 and D-α-Tocopherol polyethylene glycol 1000 succinate, offer an innovative solution to enhance juglone's therapeutic potential while minimizing toxicity. In-vitro studies have demonstrated that micelle-formulated juglone (JM) effectively decreases proliferation and migration and increases apoptosis in pancreatic cancer cell lines. Importantly, in-vivo, JM exhibited no toxicity, allowing for increased dosing frequency compared to free drug administration. In mice, JM significantly reduced tumor growth in subcutaneous xenograft and orthotopic pancreatic cancer models. Beyond its direct antitumor effects, JM treatment also influenced the tumor microenvironment. In immunocompetent mice, JM increased immune cell infiltration and decreased stromal deposition and activation markers, suggesting an immunomodulatory role. To understand JM's mechanism of action, we conducted RNA sequencing and subsequent differential expression analysis on tumors that were treated with JM. The administration of JM treatment reduced the expression levels of the oncogenic protein MYC, thereby emphasizing its potential as a focused, therapeutic intervention. In conclusion, the polymeric micelles-mediated delivery of juglone holds excellent promise in pancreatic cancer therapy. This approach offers improved drug delivery, reduced toxicity, and enhanced therapeutic efficacy.

The accurate prediction of non-cirrhotic hepatocellular carcinoma (NCHCC) risk facilitates improved surveillance strategy and decreases cancer-related mortality. This study aimed to explore the correlation between immunogenic cell death (ICD) and NCHCC prognosis using The Cancer Genome Atlas (TCGA) datasets, and the potential prognostic value of ICD-related genes in NCHCC.

Clinical and transcriptomic data of patients with NCHCC patients were retrieved from TCGA database. Weighted gene co-expression network analysis was performed to obtain the NCHCC phenotype-related module genes. Consensus clustering analysis was performed to classify the patients into two clusters based on intersection genes among differentially expressed genes (DEGs) between cancer and adjacent tissues, NCHCC phenotype-related genes, and ICD-related genes. NCHCC-derived tissue microarray was used to evaluate the correlation of the expression levels of key genes with NCHCC prognosis using immunohistochemical staining.

Cox regression analyses were performed to construct a prognostic risk score model comprising three genes (TMC7, GRAMD1C, and GNPDA1) based on DEGs between two clusters. The model stratified patients with NCHCC into two risk groups. The overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. Univariable and multivariable Cox regression analyses revealed that these signature genes are independent predictors of OS. Functional analysis revealed differential immune status between the two risk groups. Next, a nomogram was constructed, which demonstrated the potent distinguishing ability of the developed model based on receiver operating characteristic curves. In vitro functional validation revealed that the migration and invasion abilities of HepG2 and Huh7 cells were upregulated upon GRAMD1C knockdown but downregulated upon TMC7 knockdown.

This study developed a prognostic model comprising three genes, which can aid in predicting the survival of patients with NCHCC and guide the selection of drugs and molecular markers for NCHCC.

Tumor vaccines have been used to treat cancer. How to efficiently induce tumor-associated antigens (TAAs) secretion with host immune system activation is a key issue in achieving high antitumor immunity. Immunogenic cell death (ICD) is a process in which tumor cells upon an external stimulus change from non-immunogenic to immunogenic, leading to enhanced antitumor immune responses. The immune properties of ICD are damage-associated molecular patterns and TAA secretion, which can further promote dendritic cell maturation and antigen presentation to T cells for adaptive immune response provocation. In this review, we mainly summarize the latest studies focusing on nanotechnology-mediated ICD for effective cancer immunotherapy as well as point out the challenges.

MicroRNA (miRNA) has been widely used as an effective gene drug for tumor therapy, but its chemical instability limited its therapeutic application in vivo. In this research, we fabricate an efficient miRNA nano-delivery system using zeolitic imidazolate framework-8 (ZIF-8) coated with bacterial outer membrane vesicles (OMVs), aimed for cancer treatment. The acid-sensitive ZIF-8 core enables this system to encapsulate miRNA and release them from lysosome quickly and efficiently in the target cells. The OMVs engineered to display programmed death receptor 1 (PD1) on the surface provides a specific tumor-targeting capability. Using a murine breast cancer model, we show that this system has high miRNA delivery efficiency and accurate tumor targeting. Moreover, the miR-34a payloads in carriers can further synergize with immune activation and checkpoint inhibition triggered by OMV-PD1 to enhance tumor therapeutic efficacy. Overall, this biomimetic nano-delivery platform provides a powerful tool for the intracellular delivery of miRNA and has great potential in RNA-based cancer therapeutic applications.

Zn1 and Zn2 are Zn-based complexes that activate the immunogenic cell death (ICD) effect by Ca2+-mediated endoplasmic reticulum stress (ERS) and mitochondrial dysfunction. Compared with Zn1, Zn2 effectively caused reactive oxidative species (ROS) overproduction in the early phase, leading to ERS response. Severe ERS caused the release of Ca2+ from ER to cytoplasm and further to mitochondria. Excessive Ca2+ in mitochondria triggered mitochondrial dysfunction. The damage-associated molecular patterns (DAMPs) of CRT, HMGB1, and ATP occurred in T-24 cells exposed to Zn1 and Zn2. The vaccination assay demonstrated that Zn1 and Zn2 efficiently suppressed the growth of distant tumors. The elevated CD8+ cytotoxic T cells and decreased Foxp3+ cells in vaccinated mice supported our conclusion. Moreover, Zn1 and Zn2 improved the survival rate of mice compared with oxaliplatin. Collectively, our findings provided a new design strategy for a zinc-based ICD inducer via ROS-induced ERS and mitochondrial Ca2+ overload.

Immunotherapy has developed rapidly in solid tumors, especially in the areas of blocking inhibitory immune checkpoints and adoptive T-cell transfer for immune regulation. Many patients benefit from immunotherapy. However, the response rate of immunotherapy in the overall population are relatively low, which depends on the characteristics of the tumor and individualized patient differences. Moreover, the occurrence of drug resistance and adverse reactions largely limit the development of immunotherapy. Recently, the emergence of nanodrug delivery systems (NDDS) seems to improve the efficacy of immunotherapy by encapsulating drug carriers in nanoparticles to precisely reach the tumor site with high stability and biocompatibility, prolonging the drug cycle of action and greatly reducing the occurrence of toxic side effects. In this paper, we mainly review the advantages of NDDS and the mechanisms that enhance conventional immunotherapy in solid tumors, and summarize the recent advances in NDDS-based therapeutic strategies, which will provide valuable ideas for the development of novel tumor immunotherapy regimen.

Cancer immunotherapies have improved human health, and one among the important technologies for cancer immunotherapy is cancer vaccine. Antigens are the most important components in cancer vaccines. Generally, antigens in cancer vaccines can be divided into two categories: pre-defined antigens and unidentified antigens. Although, cancer vaccines loaded with predefined antigens are commonly used, cancer vaccine loaded with mixed unidentified antigens, especially whole cancer cells or cancer cell lysates, is a very promising approach, and such vaccine can obviate some limitations in cancer vaccines. Their advantages include, but are not limited to, the inclusion of pan-spectra (all or most kinds of) antigens, inducing pan-clones specific T cells, and overcoming the heterogeneity of cancer cells. In this review, the recent advances in cancer vaccines based on whole-tumor antigens, either based on whole cancer cells or whole cancer cell lysates, are summarized. In terms of whole cancer cell lysates, the focus is on applying whole water-soluble cell lysates as antigens. Recently, utilizing the whole cancer cell lysates as antigens in cancer vaccines has become feasible. Considering that pre-determined antigen-based cancer vaccines (mainly peptide-based or mRNA-based) have various limitations, developing cancer vaccines based on whole-tumor antigens is a promising alternative.

Immune checkpoint blockade, especially the programmed cell death ligand 1 (PD-L1) blockade, has revolutionized the treatment of melanoma. However, PD-1/PD-L1 monotherapy leads to unsatisfactory therapeutic outcomes. The immunotherapy of melanoma could be improved by adding doxorubicin (DOX), which triggers immunogenic cell death (ICD) effect to activate anti-tumor immunity. Additionally, microneedles, especially dissolving microneedles (dMNs), can further enhance outcomes of chemo-immunotherapy due to the physical adjuvant effect of dMNs. Herein, we developed the dMNs-based programmed delivery system that incorporated pH-sensitive and melanoma-targeting liposomes to co-deliver DOX and siPD-L1, achieving enhanced chemo-immunotherapy of melanoma (si/DOX@LRGD dMNs). The incorporated si/DOX@LRGD LPs demonstrated uniform particle size, pH-sensitive drug release, high in vitro cytotoxicity and targeting ability. Besides, si/DOX@LRGD LPs effectively downregulated the expression of PD-L1, induced tumor cell apoptosis and triggered ICD effect. The si/DOX@LRGD LPs also showed deep penetration (approximately 80 μm) in 3D tumor spheroids. Moreover, si/DOX@LRGD dMNs dissolved rapidly into the skin and had sufficient mechanical strength to penetrate skin, reaching a depth of approximately 260 μm in mice skin. In mice model of melanoma tumor, si/DOX@LRGD dMNs exhibited better anti-tumor efficacy than monotherapy by dMNs and tail intravenous injection at the same dose. This was due to the higher cytotoxic CD8+ T cells and the secreted cytotoxic cytokine IFN-γ evoked by si/DOX@LRGD dMNs, thereby eliciting strong T-cell mediated immune response and resulted in enhanced anti-tumor effects. In conclusion, these findings suggested that si/DOX@LRGD dMNs provided a promising and effective strategy for enhanced chemo-immunotherapy of melanoma.

The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications which allow enhanced presentation of tumor antigen and neighboring dendritic cell activation. Furthermore, DOX also facilitate the immune-mediated clearance of tumor cells. However, disadvantages such as severe off-target toxicity, and prominent hydrophobicity have resulted in unsatisfactory clinical therapeutic outcomes. The effective delivery of DOX drug molecules is still challenging despite the rapid advances in nanotechnology and biomaterials. Huge progress has been witnessed in DOX nanoprodrugs owing to their brilliant benefits such as tumor stimuli-responsive drug release capacity, high drug loading efficiency and so on. This review summarized recent progresses of DOX prodrug-based nanomedicines to provide deep insights into future development and inspire researchers to explore DOX nanoprodrugs with real clinical applications.

Clear cell renal cell carcinoma (ccRCC) is a prevalent urological malignancy associated with a high mortality rate. The lack of a reliable prognostic biomarker undermines the efficacy of its predictive, preventive, and personalized medicine (PPPM/3PM) approach. Immunogenic cell death (ICD) is a specific type of programmed cell death that is tightly associated with anti-cancer immunity. However, the role of ICD in ccRCC remains unclear.

Based on AddModuleScore, single-sample gene set enrichment analysis (ssGSEA), and weighted gene co-expression network (WGCNA) analyses, ICD-related genes were screened at both the single-cell and bulk transcriptome levels. We developed a novel machine learning framework that incorporated 10 machine learning algorithms and their 101 combinations to construct a consensus immunogenic cell death-related signature (ICDRS). ICDRS was evaluated in the training, internal validation, and external validation sets. An ICDRS-integrated nomogram was constructed to provide a quantitative tool for predicting prognosis in clinical practice. Multi-omics analysis was performed, including genome, single-cell transcriptome, and bulk transcriptome, to gain a more comprehensive understanding of the prognosis signature. We evaluated the response of risk subgroups to immunotherapy and screened drugs that target specific risk subgroups for personalized medicine. Finally, the expression of ICD-related genes was validated by qRT-PCR.

We identified 131 ICD-related genes at both the single-cell and bulk transcriptome levels, of which 39 were associated with overall survival (OS). A consensus ICDRS was constructed based on a 101-combination machine learning computational framework, demonstrating outstanding performance in predicting prognosis and clinical translation. ICDRS can also be used to predict the occurrence, development, and metastasis of ccRCC. Multivariate analysis verified it as an independent prognostic factor for OS, progression-free survival (PFS), and disease-specific survival (DSS) of ccRCC. The ICDRS-integrated nomogram provided a quantitative tool in clinical practice. Moreover, we observed distinct biological functions, mutation landscapes, and immune cell infiltration in the tumor microenvironment between the high- and low-risk groups. Notably, the immunophenoscore (IPS) score showed a significant difference between risk subgroups, suggesting a better response to immunotherapy in the high-risk group. Potential drugs targeting specific risk subgroups were also identified.

Our study constructed an immunogenic cell death-related signature that can serve as a promising tool for prognosis prediction, targeted prevention, and personalized medicine in ccRCC. Incorporating ICD into the PPPM framework will provide a unique opportunity for clinical intelligence and new management approaches.

The online version contains supplementary material available at 10.1007/s13167-023-00327-3.

Despite immunotherapy emerging as a vital approach to improve cancer treatment, the activation of efficient immune responses is still hampered by immunosuppression, especially due to the low tumor immunogenicity. Immunogenic cell death (ICD) is a promising strategy to reshape the tumor microenvironment (TME) for achieving high immunogenicity. Various stimuli are able to effectively initiate their specific ICD by utilizing the corresponding ICD-inducer. However, the ICD-guided antitumor immune effects are usually impaired by various biological barriers and TME-associated immune resistance. Biomimetic active materials are being extensively explored as guided agents for ICD due to their unique advantages. In this review, two major strategies are systematically introduced that have been employed to exploit biomimetic active materials guided ICD for cancer immunotherapy, mainly including naive organism-derived nanoagents and engineered bioactive platforms. This review outlines the recent advances in the field at biomimetic active materials guided physiotherapy, chemotherapy, and biotherapy for ICD induction. The advances and challenges of biomimetic active materials guided ICD for cancer immunotherapy applications are further discussed in future clinical practice. This review provides an overview of the advances of biomimetic active materials for targeting immunoregulation and treatment and can contribute to the future of advanced antitumor combination therapy.

Immunotherapy is considered to be one of the most promising methods to overcome cancer. Immunogenic cell death (ICD), as a special form of cell death that can trigger an antitumor immune response, has attracted increasing attention for cancer immunotherapy. Presently, ICD-mediating immunotherapy needs to overcome many hurdles including a lack of targeted delivery systems for ICD inducers, insufficient antitumor immunity, and the immunosuppressive tumor microenvironment. Recent research has demonstrated that nano-biomaterials exhibit unique biochemphysical properties at the nanoscale, providing a prospective approach to overcoming these obstacles. In this review, the authors first survey the occurrence, processes, and detection methods of ICD. Subsequently, the recent advances of nano-biomaterials applied to enhance ICD according to the key steps in the process of ICD, particularly with a focus on the mechanisms and lifting schemes are investigated. Finally, based on the achievement in the representative studies, the prospects and challenges of nanotechnology in ICD for cancer therapy are discussed to enable clinical translation.