Locally advanced rectal cancer (LARC) is treated with neoadjuvant chemo-radiotherapy (nCRT) followed by surgery. A minority of patients show complete response (CR) to nCRT and may avoid surgery and its functional consequences. Instead, most patients show non-complete response (non-CR) and may benefit from additional treatments to increase CR rates. Reliable predictive markers are lacking. Aim of this study was to identify novel signatures predicting nCRT responsiveness. We performed a combined analysis of tumor-associated microbiome and immune gene expression profiling of diagnostic biopsies from 70 patients undergoing nCRT followed by rectal resection, including 16 with CR and 54 with non-CR. Findings were validated by an independent cohort of 49 patients, including 7 with CR and 42 with non-CR. Intratumoral microbiota significantly differed between CR and non-CR groups at genus and species level. Colonization by bacterial species of Ruminococcus genera was consistently associated with CR, whereas abundance of Fusobacterium, Porhpyromonas, and Oscillibacter species predicted non-CR. Immune gene profiling revealed a panel of 59 differentially expressed genes and significant upregulation of IFN-gamma and -alpha response in patients with CR. Integrated microbiome and immune gene profiling analysis unraveled clustering of microbial taxa with each other and with immune cell-related genes and allowed the identification of a combined signature correctly identifying non-CRS in both cohorts. Thus, combined intratumoral microbiome-immune profiling improves the prediction of response to nCRT. Correct identification of unresponsive patients and of bacteria promoting responsiveness might lead to innovative therapeutic approaches based on gut microbiota pre-conditioning to increase nCRT effectiveness in LARC.

Apoptosis is vital for improving the efficacy of lung cancer (LC) immunotherapy by targeting cancer cell elimination. Despite its importance, there is a lack of comprehensive bibliometric studies analyzing global research on apoptosis in LC immunotherapy. This analysis aims to address this gap by highlighting key trends, contributors, and future directions. A total of 969 publications from 1996 to 2024 were extracted from the Web of Science Core Collection. Analysis was conducted using VOSviewer, CiteSpace, and the R package 'bibliometrix.' The study included contributions from 6,894 researchers across 1,469 institutions in 61 countries, with research published in 356 journals. The volume of publications has steadily increased, led by China and the United States, with Sichuan University as the top contributor. The journal Cancers published the most articles, while Cancer Research had the highest co-citations. Yu-Quan Wei was the leading author, and Jemal, A. was the most frequently co-cited. Key research themes include "cell death mechanisms," "immune regulation," "combination therapies," "gene and nanomedicine applications," and "traditional Chinese medicine (TCM)." Future research is likely to focus on "coordinated regulation of multiple cell death pathways," "modulation of the tumor immune microenvironment," "optimization of combination therapies," "novel strategies in gene regulation," and the "integration of TCM" for personalized treatment. This is the first bibliometric analysis on the role of apoptosis in LC immunotherapy, providing an landscape of global research patterns and emerging therapeutic strategies. The findings offer insights to guide future research and optimize treatment approaches.

Durable clinical responses to immune checkpoint inhibitors (ICI) are limited to a minority of patients, and molecular pathways that modulate their efficacy remain incompletely defined. We have recently shown that activation of the innate RNA-sensing receptor RIG-I and associated apoptotic tumor cell death can facilitate tumor immunosurveillance and -therapy, but the mechanism that drives its immunogenicity remained unclear. We here show that intratumoral activity of the pore-forming protein gasdermin E (GSDME) links active RIG-I signaling and apoptotic cell death in tumor cells to inflammatory pyroptosis. Activation of tumor-intrinsic RIG‑I triggered cleavage of GSDME, pore formation, loss of cell membrane integrity and leakage of cytosolic components from dying tumor cells. Tumor antigen cross-presentation by dendritic cells and subsequent expansion of cytotoxic T cells strongly relied on tumor-intrinsic GSDME activity. In preclinical murine cancer models, defective GSDME signaling rendered tumors resistant to ICI therapy. Epigenetic reprogramming with upregulation of Gdsme enhanced the susceptibility of tumor cells to inflammatory cell death and immunotherapy. In humans, transcriptome analysis of melanoma samples showed strong correlation between genetic activity of the RIG-I and pyroptosis pathways. In melanoma patients, high transcriptional activity of a pyroptosis gene set was associated with prolonged survival and beneficial response to ICI therapy. In summary, our data show that GSDME links RIG-I and apoptotic signaling to inflammatory cell death, thereby driving its immunogenicity and responsiveness to ICI. A deeper understanding of these pathways may allow for the development of novel combined modality approaches to improve ICI treatment responses in cancer patients.

Effective cancer immune therapy requires the orchestration of antigen induction, presentation and T-cell activation, further enhanced by anti-angiogenesis treatment; therefore, multiple therapeutics are generally used for such combination therapy. Herein, we report esterase-hydrolysable cationic polymers, N-[3-((4-acetoxy benzyl) oxy)-3-oxopropyl]-N-methyl-quaternized PEI (ERP) and poly{N-[2-(acryloyl-oxy) ethyl]-N-[p-acetyloxyphenyl]-N,N-dimethylammonium chloride} (PQDMA), capable of simultaneously inducing tumor cell immunogenic cell death (ICD) to release antigens, activating the cGAS-STING pathways of tumor macrophages and dendritic cells, and releasing antiangiogenic agent p-hydroxybenzyl alcohol (HBA). Thus, intratumoral injection of ERP or PQDMA systemically boosted the anti-cancer immunities and inhibited tumor angiogenesis in mouse hepatocellular carcinoma and melanoma bilateral tumor models, leading to more effective tumor growth inhibition of both treated and abscopal untreated tumors than ICD alone induced by mitoxantrone and control cationic polymers. Further study using gene knockout mice and transcriptome sequencing analysis confirmed the involvement of cGAS-STING and type I IFN signaling pathways. This work demonstrates ERP and PQDMA as the first examples of inherent therapeutic polymers, accomplishing systemic tumor inhibition without combining other therapeutic agents.

The strategy of inducing tumors to release damage-associated molecular patterns (DAMPs) to trigger immunogenic cell death has garnered significant attention in cancer therapy. However, the hypoxic tumor microenvironment, which is often programmed by cancer cells, results in the release of immunosuppressive DAMPs (iDAMPs), which substantially influence antitumor immune responses. In this study, we developed a redox-responsive carboxymethyl chitosan (CMC)-based nanoplatform for the sequential delivery of a hypoxia-inducible factor 1-α (HIF-1α) inhibitor, 3-(5'-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1), and the chemotherapeutic agent doxorubicin (DOX), aimed to restore therapeutic sensitization and immunostimulation in tumors. The preferential release of YC-1 effectively targets the HIF-1α/cyclooxygenase-2 (COX-2) axis, significantly reducing the secretion of immunosuppressive factor prostaglandin E2 (PGE2), thereby resensitizing tumors to Tcell-mediated immunity. Additionally, YC-1 mitigates hypoxia-induced tumor chemoresistance by inhibiting the HIF-1α/P-glycoprotein (P-gp) axis, further improving the immunotherapeutic efficacy of DOX. Our work demonstrates that regulating hypoxia-induced immunosuppressive factors in tumors contributes to the inhibition of both primary and metastatic tumors, offering a promising approach to enhance immunotherapies.

A significant challenge in the treatment of melanoma with immune checkpoint blockades (ICBs) is the limited T cells response often observed in immunologically "cold" tumors. By leveraging the immunogenicity of immunogenic cell death (ICD), which increases the susceptibility of tumor cells to ICBs, this study investigated the potential of a nucleus-targeted ruthenium(II) complex (Ru1) as an inducer of ICD. Treatment with Ru1 induced DNA damage in melanoma cells, activating the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway. This triggered endoplasmic reticulum (ER) stress, leading to ICD. Ru1-treated dying melanoma cells exhibited characteristics such as cell exposure of calreticulin (CRT) on the cell surface, release of adenosine triphosphate (ATP), and secretion of high-mobility group box 1 (HMGB1). Vaccination with Ru1-treated, dying melanoma cells elicited robust antitumor immune responses, as evidenced by CD8+ T cells activation, reduced Foxp3+ T cells count, and the development of a memory immune response that protected mice from subsequent melanoma challenges. Combining Ru1 with anti-PD-1 therapy significantly promoted T cells infiltration, enhanced dendritic cell activation, and reduced tumor-associated immunosuppressive factors, indicating a reprogramming of the tumor microenvironment. These findings suggest that Ru1 is a promising therapeutic agent for treating "cold" tumors in cancer chemoimmunotherapy.

Owing to the excellent stability, anticancer activity and immunogenicity, peroxynitrite (ONOO-) has been gained enormous interests in cancer therapy. Nevertheless, precise delivery and control release of ONOO- in tumors remains a big challenge. Herein, B16F10 cancer cell membrane/liposome hybrid membrane (CM-Lip) based biomimetic nanodrug with high-efficient tumor-homing and NIR-II laser controlled ONOO- boost properties was designed for melanoma treatment. Briefly, NIR-II molecule IR1061, NO donor BNN6 and β-lapachone (Lapa) were firstly encapsulated in the heat-responsive palmitoyl phosphatidylcholine/cholesterol liposome, followed by fusion with B16F10 cell membrane (CM) to obtain biomimetic CM-Lip@(IR/BNN6/Lapa). The hybrid membrane-based nanodrug displayed excellent biocompatibility and melanoma-targeting efficiency. Upon 1064 nm laser irradiation, the mild photothermal effect of CM-Lip@(IR/BNN6/Lapa) firstly triggered the release of NO and Lapa, which subsequently catalyzed the quinone oxidoreductase 1 (NQO1) overexpressed in tumors to produce O2•-, finally caused intraturmal ONOO- boost via cascade reaction. The boosted ONOO- could effectively inhibit melanoma by ways of triggering mitochondrion-mediated apoptotic pathway, upregulating 3-nitrotyrosine expression, inducing DNA damage and inhibiting DNA repair enzyme expression of poly (ADP-ribose) polymerase 1 (PARP-1). Moreover, ONOO- displayed excellent immunoactivation and immunomodulation activities by effectively inducing immunogenic tumor cell death, promoting dendritic cells maturation, increasing cytotoxic T lymphocytes expression and repolarizing M1-phenotype macrophages.

Calreticulin (CALR) preserves reticular homeostasis by maintaining correct protein folding within the endoplasmic reticulum. Immunogenic cell death (ICD) is a regulated form of cell death and could activate adaptive immune response. As one of the damage-associated molecular patterns during ICD process, surface-exposed CALR resulted in the activation of adaptive immune response. Here, we evaluated the expression patterns of CALR in a cohort of 231 untreated triple-negative breast cancer (TNBC) and determined correlations between CALR expression and clinicopathologic parameters, programmed cell death ligand 1 (PD-L1) expression in immune cells (ICs), and survival. In addition, we analyzed a TNBC data set from The Cancer Genome Atlas to explore the relationship between mRNA expression of CALR and clinicopathologic features, IC infiltration, and survival. Tissue microarray results showed that high CLAR was strongly correlated with advanced stage ( P = 0.022), shorter disease-free survival ( P = 0.008) and overall survival ( P = 0.002), and independently predicted prognosis in TNBC. Spearman analyses demonstrated that CALR negatively correlated with PD-L1 in ICs ( r = -0.198, P = 0.003). Patients with low CALR and high PD-L1 in ICs had the best disease-free survival ( P = 0.013) and overall survival ( P = 0.004) compared with other patients, especially the patients with high CALR and low PD-L1 in ICs. In the "The Cancer Genome Atlas" cohort, CALR mRNA expression in tumors was significantly higher than that in normal tissues ( P < 0.001). CALR expression was strongly and positively related to other ICD-related genes. These findings demonstrated that the expression of CALR could independently predict the prognosis in patients with TNBC, and it may play a potential synergistic role in treatments involving immunotherapy.

Current cancer treatment strategies in practice nowadays often face limitations in effectiveness due to factors such as resistance, recurrence, or suboptimal outcomes. Traditional approaches like chemotherapy often come with severe systemic side effects due to their non-specific action, prompting the development of more targeted therapies. Among these, physical ablation techniques such as radiotherapy (RT) and focused ultrasound (FUS) have gained attention for their ability to precisely target malignant tissues, reduce physical and mental stress for the patients, and minimize recovery time. These therapies also aim to stimulate the immune system through a process referred to as immunogenic cell death (ICD), enhancing the body's ability to fight cancer, explaining abscopal effects. RT has been the most established of the abovementioned techniques for decades, and will not be included in the review. While initially focused on complete tumor ablation, these techniques are now shifting towards milder, more controlled applications that induce ICD without extensive tissue damage. This review explores how physical ablation therapies can harness ICD to boost anticancer immunity, emphasizing their potential to complement immunotherapies and improve outcomes for cancer patients.

The development of antibiotic resistance and inadequate immune response in chronic inflammation pose significant challenges in treating chronic osteomyelitis. As accepted non-antibiotic antimicrobial therapies, sonodynamic therapy (SDT) and photothermal therapy (PTT) are recognized for their effectiveness in eliminating bacteria and promoting tissue repair, rendering them promising therapeutic strategies for treating bacterial infections and preventing the emergence of drug-resistant bacteria. However, the antimicrobial action and efficacy in promoting tissue repair depend on the activation status of the host immune system. In this study, by encapsulating horseradish peroxidase (HRP)-loaded gold/polydopamine (PDA) nanoparticles within DOTAP/DOPE cationic liposomes (DLPs), a novel multifunctional nanocatalyst, Au/PDA/HRP@DLP (APH@DLP), was developed to achieve antimicrobial effects and immunological reprogramming of chronic osteomyelitis through synergistic SDT and PTT. The impact on immune activation was investigated by assessing the anti-infective and healing effects in osteomyelitis rat models. The release of bacterial-associated antigens during treatment serves as an in situ vaccine, activating antigen-presenting cells and further stimulating adaptive immunity, while also inducing immune memory that significantly reduces the risk of recurrence. Additionally, macrophage phenotypic transformation during SDT and PTT facilitates tissue repair. This study highlights the role of immune activation in SDT/PTT-based antimicrobial therapy and suggests new strategies for treating chronic osteomyelitis.

Cuproptosis, a recently recognized regulated cell death, distinct from established death mechanisms, offers promising cancer therapy. However, its efficacy relies on intracellular copper availability and homeostasis. Herein, a novel Copper(II) dipyridohenazine complex, Cu(L1)2Cl acts as an oxidative stress amplifier and glutathione (GSH) disrupter for synergistic cuproptosis/chemodynamic anticancer therapy for the treatment of challenging triple negative breast cancer. Cu(L1)2Cl followed the endocytosis pathway to enter tumor cells and depleted GSH to release Cu+ ions which result in the production of.OH radicals generated from H2O2, leading to chemodynamic therapy. The spike in ROS generation disrupts cellular redox homeostasis, causing impaired mitochondrial function, ATP depletion, and endoplasmic reticulum stress generation. ATP depletion directly affects the function of copper-transporting ATPase 1 (ATP7A), resulting in a large amount of Cu+ trapped inside cancer cells, causing oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), and depletion of Lipoyl synthase (LIAS), and leading to cellular cuproptosis. Subsequently, Cu(L1)2Cl interrupts tumor metastasis and evokes immunogenic cell death (ICD) by promoting high mobility group protein (HMGB1), ATP and lactate dehydrogenase (LDH) release, calreticulin (CRT) exposure, and inhibiting programmed death ligand 1 (PD-L1). The in vivo studies on 4T1 tumor bearing Balb/c mice validate its potent antitumor efficacy, thereby providing a new therapeutic paradigm to augment cuproptosis-related therapies.

In recent years, the rapid development of nanoparticle adjuvants has greatly facilitated the treatment and prevention of infectious diseases in humans and animals. The remarkable success of mRNA nanovaccines against SARS-CoV-2 has accelerated the advancement of nanoparticle adjuvant technologies in the era of precision medicine. Significant progress has been made in researching nanovaccines for major animal infectious diseases, such as porcine epidemic diarrhea, avian influenza, porcine reproductive and respiratory syndrome, bovine viral diarrhea, foot-and-mouth disease, African swine fever, and Newcastle disease. This article reviews the nanoparticle adjuvants under investigation for animal use, emphasizing their diverse mechanisms of action and immunological properties, and analyzes the physicochemical factors influencing their immune-enhancing effects. On this basis, we discuss future prospects and key challenges that need to be addressed, aiming to provide valuable references for the development of novel animal vaccine adjuvants.

Immune checkpoint inhibitors (ICIs) of programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) reinvigorate strong polyclonal T-cell immune responses against tumor cells. For many patients, these therapies fail because the development of spontaneous immune responses is often compromised, as the tumor microenvironment (TME) lacks proinflammatory signals resulting in suboptimal activation of antigen-presenting cells (APCs). Necroptosis is a special form of programmed cell death associated with leakage of inflammatory factors that can lead to APC maturation. However, it is unclear to which extent functional necroptosis in tumor cells contributes to ICI immunotherapy.

With genetically engineered tumor cell lines that lack specific components of the necroptosis machinery (mixed lineage kinase domain-like pseudokinase (MLKL), receptor interacting protein kinase 3 (RIPK3)), we addressed the importance of necroptotic tumor cell death for the efficacy of ICI immunotherapy in murine models. Preclinical data were aligned with genome-wide transcriptional programs in patient tumor samples at diagnosis and during ICI treatment for the activity of these pathways and association with treatment outcome.

Mice bearing MLKL-deficient or RIPK3-deficient tumors failed to control tumor growth in response to anti-PD-1/anti-CTLA-4 immunotherapy. Mechanistically, defects in the necroptosis pathway resulted in reduced tumor antigen cross-presentation by type 1 conventional dendritic cells (DCs) in tumor-draining lymph nodes, and subsequently impaired immunotherapy-induced expansion of circulating tumor antigen-specific CD8+ T cells and their accumulation and activation in the TME. In vitro, co-culture of tumor cells undergoing necroptotic but not apoptotic programmed cell death resulted in increased uptake by phagocytic cells, associated with maturation and activation of DCs. Treatment of tumors with the epigenetic modulator azacytidine enhanced intrinsic transcriptional activity of the necroptosis machinery, and hence their susceptibility to ICI immunotherapy. In humans, transcriptome analysis of melanoma samples revealed a strong association between high expression of MLKL and prolonged overall survival and durable clinical response to immunotherapy with anti-PD-1 and/or anti-CTLA-4 checkpoint inhibitors.

Defective necroptosis signaling in tumor cells is a cancer resistance mechanism to ICI immunotherapy. Reversion of epigenetic silencing of the necroptosis pathway can render tumors susceptible to checkpoint inhibition.

Vaccines usually contain an adjuvant that activates innate immunity to promote the acquisition of adaptive immunity. Aluminum and lipid nanoparticles have been used for this purpose, but their accumulation or widespread circulation in the body can lead to adverse effects. In contrast, physical adjuvants, which use physical energy to transiently stress tissues, do not persist in exposed tissues or cause lasting adverse effects. Herein, we investigate the effects of intradermal injection of endotoxin-free ovalbumin (OVA) protein alone without additional adjuvants using a needle-free pyro-drive jet injector (PJI) on tumor vaccination efficacy. Intradermal injection of OVA protein alone using PJI significantly increased OVA-specific CD8+ T cell expansion in the lymph node, although lymph node swelling was much less than when aluminum hydroxide was used. The injection also induced OVA-specific killing activity and antibody production and showed strong CD8+ T cell-dependent prophylactic antitumor effects against transplanted E.G7-OVA tumors. In particular, intradermal injection of the fluorescent OVA protein significantly enhanced its uptake by XCR1+ dendritic cells, which have a strong ability to cross-present extracellular proteins in the skin and draining lymph nodes. In addition, the injection increased the expression of HMGB1, one of the potent danger signals whose expression has been reported to increase in response to shear stress. Thus, intradermal injection of OVA protein alone without any additional adjuvants using PJI induces potent CD8+ T cell-mediated antitumor immunity by enhancing its uptake into XCR1+ dendritic cells, which have a high cross-presentation capacity accompanied by an increased expression of shear stress-induced HMGB1.

Extracellular vesicles (EVs), which are secreted by various cell types, hold significant potential for cancer therapy. However, there are several challenges and difficulties that limit their application in clinical settings. This review, which integrates the work of our team and recent advancements in this research field, discusses EV-based cancer treatment strategies to guide their clinical application. The following treatment strategies are discussed: 1) leveraging the inherent properties of EVs for the development of cancer treatments; 2) modifying EVs using EV engineering methods to improve drug loading and delivery; 3) targeting key molecules in tumor-derived EV (TDE) synthesis to inhibit their production; and 4) clearing TDEs from the tumor microenvironment. Additionally, on the basis of research into EV-based vaccines and bispecific antibodies, this review elaborates on strategies to enhance antitumor immunity via EVs and discusses engineering modifications that can improve EV targeting ability and stability and the research progress of AI technology in targeted delivery of EV drugs. Although there are limited strategies for enhancing EV targeting abilities, this review provides an in-depth discussion of prior studies. Finally, this review summarizes the clinical progress on the use of EVs in cancer therapy and highlights challenges that need to be addressed.

Antibody-drug conjugates (ADCs) are a promising cancer therapy for targeted delivery of drugs to tumor cells. However, resistance to ADCs remains a challenge, necessitating the exploration of combination therapies. A strong biological theory suggests that ADCs interact with cancer cells and immune cells by triggering mechanisms such as immunogenic cell death, dendritic cell activation, and memory T-cell activation, resulting in long-term anti-tumor immunity and ultimately potential synergistic effects with immunotherapy. Based on extensive and reliable preclinical data, several clinical trials are currently combining ADCs with immune checkpoint inhibitors (ICIs) for the treatment of various cancers, including breast, gastric, and non-small-cell lung cancers, to evaluate the safety and anti-tumor activity of the combination therapy. Preliminary evidence from early clinical trials has reported more effective efficacy data. This paper reviews the combination of ADCs and immunotherapy, highlights the key mechanisms by which the two act synergistically, and summarizes the available clinical evidence against different ADCs targets. The paper also explores the re-challenges used for combination therapies and optimized design options for ADCs drugs.

Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.

Cervical cancer is a common tumor in women and one of the common causes of cancer death in women. Due to the aggressive and non-specific nature of traditional chemotherapy, there is a growing need for new treatment modalities. Currently, tumor immunotherapy is increasingly garnering attention as a disruptive treatment approach. Therefore, we constructed CCTP-SmacN7, a delivery system capable of releasing active molecules in the tumor microenvironment. CCTP-SmacN7 can not only inhibit tumor proliferation and migration, but also induce tumors to produce large amounts of reactive oxygen species. The production of reactive oxygen species can activate tumors to release or expose damage-associated molecular patterns, promote DC cell maturation, and ultimately activate T cells. Here, we present an innovative targeted treatment approach for cervical cancer. While inducing tumor immunogenic cell death, this program can also improve the tumor microenvironment and initiate the tumor immune cycle.

Thoracic radiotherapy (RT) is now widely used in the treatment of advanced non-small cell lung cancer (NSCLC) as palliative, consolidative or radical therapy. However, RT adversely impacts the immune system, which can be evaluated by calculating the estimated dose of radiation to immune cells (EDRIC). We evaluated the prognostic impact of the EDRIC in patients with advanced NSCLC who received immunotherapy and thoracic RT.

We retrospectively enrolled 152 stage IV NSCLC patients who had received first-line immunotherapy and thoracic RT. EDRIC was a model developed by Jin et al., calculated using the number of radiotherapy fractions, mean lung dose, mean heart dose, and mean body dose. Spearman's rank correlation was used to assess the correlations between variables. The relationships of EDRIC (≥5.7 Gy vs. <5.7 Gy) with survival were assessed using Kaplan-Meier and Cox proportional hazard models.

The median PFS and OS were shorter in the EDRIC ≥ 5.7 Gy group (PFS: 10.2 months vs. 18.6 months, P < .0001; OS: 19.8 months vs. 30.2 months, P = .024). In the multivariate model, higher EDRIC was associated with worse PFS (HR = 2.791, P < .0001) and OS (HR = 1.823, P = .028). Additionally, bone metastasis was associated with worse OS (HR = 1.751, P = .022).

EDRIC was an independent predictor for PFS and OS in advanced NSCLC patients receiving immunotherapy and RT. These observations necessitate further exploration into techniques to optimize radiation exposure to the immune system in cancer treatment.

Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.Abbreviation: ATG5: autophagy related 5; ATG13: autophagy related 13; DKO: double knockout; ICD: immunogenic cell death; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LGALS3: galectin 3; LDL: low-density lipoprotein; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTX: mitoxantrone; NPC1: NPC intracellular cholesterol transporter 1; NPC2: NPC intracellular cholesterol transporter 2; TFE3: transcription factor E3; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.

Bacteria-based in situ vaccination (ISV) has emerged as an effective therapeutic approach by activating anti-tumor immunity. However, inducing immunogenic cell death (ICD) and promoting effector T cell activation remain critical challenges in clinical applications of bacteria-based ISV. Here, we have developed a tumor microenvironment-activated nano-hybrid engineered bacterium as ISV. It was engineered with a blue-light response module (EL222) and self-luminous luminal hyaluronic acid (LHA) nanoparticles. Our study demonstrates that LHA generates local blue light stimulated by hydrogen peroxide, non-invasively activating the engineered Escherichia coli to produce IL-2. The engineered bacteria serve as an immunological adjuvant, promoting dendritic cell maturation, synergistically promoting T cell infiltration, and ultimately triggering a comprehensive activation of the immune system. Furthermore, when combined with the immune checkpoint inhibitor anti-PD-L1, this approach further effectively enhances cancer immunotherapy. Our results provide new strategies and promising prospects for the development of bacteria-based ISV immunotherapy. STATEMENT OF SIGNIFICANCE: This study developed a tumor microenvironment-activated nano-hybrid engineered bacteria (Ec-mIL2@LHA) as in situ vaccine for enhanced cancer immunotherapy. The LHA in bacterial vaccine non-invasively generated blue light upon stimulation by hydrogen peroxide of TME, leading to the sustained release of low-dose IL2 by engineered bacteria. In vitro and in vivo studies have demonstrated the bacterial in situ vaccine induced the immunogenic cell death and promote maturation of dendritic cells, ultimately triggering a comprehensive activation of anti-tumor immunity. After combination with anti-PD-L1, the bacterial in situ vaccine further effectively enhance cancer immunotherapy and inhibit metastasis. We provide a promising strategy to amplify antitumor immune effects by an engineered bacterial vaccine, showing potential clinical applications.

Light serves as an excellent external stimulus due to its high spatial and temporal resolution. The use of light to regulate biological processes has evolved into a vibrant field over the past decade. Employing light on chemical substances such as bioactive molecules and drug delivery systems offers a promising therapeutic approach to achieve precise control over biological processes. In this review, we provide an overview of the advancements in optochemical technologies for controlling bioactive molecules (photopharmacology) and drug delivery systems (photoresponsive drug delivery), with an emphasis on their relationship and biomedical applications. Gaining a deeper understanding of the underlying mechanisms and emerging research will facilitate the development of optochemically controlled bioactive molecules and photoresponsive drug delivery systems, further enhancing light technologies in biomedical applications.

Metal nanoparticles have been emerged as promising candidates in cancer therapy because of their large surface area, optical properties and ROS generation. Therefore, these nanoparticles are able to mediate cell death through hyperthermia, photothermal therapy and ROS-triggered apoptosis. The various metal nanoparticles including gold, silver and iron oxide nanostructures have been exploited for the theranostic application. Moreover, precision oncology and off-targeting features can be improved by metal nanoparticles. The modification of metal nanoparticles with carbohydrate polymers including chitosan, hyaluronic acid, cellulose, agarose, starch and pectin, among others can significantly improve their anti-cancer activities. Carbohydrate polymers have been idea for the purpose of drug delivery due to their biocompatibility, biodegradability and increasing nanoparticle stability. In addition, carbohydrate polymers are able to improve drug delivery, cellular uptake and sustained release of cargo. Such nanoparticles are capable of responding to the specific stimuli in the tumor microenvironment including pH and light. Furthermore, the carbohydrate polymer-modified metal nanoparticles can be utilized for the combination of chemotherapy, phototherapy and immunotherapy. Since the biocompatibility and long-term safety are critical factors for the clinical translation of nanoparticles, the modification of metal nanoparticles with carbohydrate polymers can improve this way to the application in clinic.

Peptide-based therapeutics for melanoma have received increasing attention in medical research. However, the local delivery of such therapeutics poses unique challenges. Cell-penetrating peptides (CPPs) with the ability to selectively enter cancer cells, with sufficient stability and increased endosomal escape mechanisms, can provide a new and improved delivery strategy for therapeutic agents for treating cancer.

We developed a new combination strategy for the synthesis of penetrating peptides functionalized with targeting of integrin α6. The linear peptide S5 was multimerized with 4 copies in linear sequential order spaced by GSG between each copy to yield the 4S5 peptide. The multimerized 4S5 peptide coupled with an intracellular delivery peptide (N) and endosomal escape peptide (G) was separated by a GGS spacer. This optimized peptide was called 4S5NG. The 4S5NG, EGFP or PE24 peptide-protein conjugates were purified via a C-terminal His-tag. The uptake efficacy, intracellular distribution and integrin α6-targeting ability of these 4S5NG peptides were systematically characterized via IncuCyte, flow cytometry and in vivo imaging using 4S5NG-Cy5 or 4S5NG-EGFP. Moreover, 4S5NG-incorporated Pseudomonas aeruginosa (PE24) exotoxin A generated therapeutic peptides. The antitumor efficacy and underlying mechanism were studied in cell lines and a mouse model. In addition, the effect of 4S5NG-PE24 on antitumor immunity of a healthy immune system was investigated via a mouse model.

Images of living cells and mice indicated that 4S5NG accumulated at tumor sites in vitro and in vivo and was much more effective than the S5 and 4S5 peptides. 4S5NG-PE24 induced cell pyroptosis in integrin α6-expressing melanoma through the caspase 3/gasdermin E (GSDME) signaling pathway in the absence of histological alterations in other organs. 4S5NG-PE24 also promoted the response rate of programmed cell death protein-1 (PD-1) checkpoint blockade to increase antitumor efficacy.

Collectively, these results highlight the potential use of 4S5NG to deliver the toxin PE24 to selectively eliminate integrin α6+ cells in melanoma, which may represent a novel treatment approach for melanoma patients.

Radiotherapy, although widely used for cancer therapy, always triggers changes in tumor microenvironment (TME) that lead to radioresistance and immunosuppression. In particular, during X-ray irradiation, hypoxia exacerbation would reduce radiosensitivity of tumor cells, while programmed cell death ligand 1 (PD-L1) upregulation impairs antitumor immune responses and exacerbates DNA damage repair, collectively resulting in severe T cell exhaustion and unsatisfactory therapeutic effect. Herein, we developed a liposomal nanodrug, C/J-LipoRGD, to simultaneously encapsulate a biological enzyme and a bromodomain containing 4 (BRD4) inhibitor for tumor-targeting delivery and TME modulation. Among C/J-LipoRGD, catalase could catalyze the decomposition of the excess H2O2 in tumors and improve TME oxygenation. Meanwhile, JQ1 as a BRD4 inhibitor after being taken by cancer cells could downregulate PD-L1 expression in both cellular membrane and cytosol, inhibiting PD-1/PD-L1 interaction and DNA damage repair. By alleviating hypoxia and downregulating PD-L1 expression, C/J-LipoRGD reverses T cell exhaustion in TME. Altogether, C/J-LipoRGD-based radiotherapy significantly inhibited tumor growth and meanwhile triggered immunogenic cell death (ICD) of cancer cells to activate T cell-mediated anti-tumor immunity. After the combination with αPD-1, C/J-LipoRGD-based radio-immunotherapy achieved complete tumor eradication and metastases elimination in 80 % mice with survival over 80 days. This multifunctional nanodrug represents a promising strategy to overcome therapy resistance and optimize radio-immunotherapy outcomes.

Boron Neutron Capture Therapy (BNCT) is an emerging modality for cancer treatment. Although its concept was proposed in the last century, progress has been relatively slow due to limitations in neutron source technology and boron compounds. In recent years, with the increased availability of neutron devices and improvements in boron compounds, the radiobiological effects of BNCT have been investigated more deeply, leading to a surge of research findings in the field. Therefore, a systematic review of the current status of BNCT is particularly warranted. In this review, we integrate the latest studies to provide a comprehensive and detailed description of the direct and indirect mechanisms by which BNCT induces cell killing, as well as the subsequent cellular responses. More importantly, we propose that BNCT exhibits a stronger immunological foundation and immunogenicity compared to traditional radiotherapy, indicating significant potential for its combined application with immunotherapy. These results offer a robust theoretical foundation for the future clinical use of BNCT and indicate that continued investigation of BNCT in conjunction with immunotherapy may pave the way for more advanced cancer treatment strategies.

Escape from apoptosis is one of the main hallmarks of cancer. The imbalance of BCL-2 family members is a key factor leading to radiotherapy resistance. Targeting BCL-2 can overcome radiotherapy resistance by promoting apoptosis. Nevertheless, the function of BCL-2 in regulating the tumor immune microenvironment (TIME) is still not well understood. Herein, we discovered that the specific BCL-2 inhibitor sonrotoclax (BGB-11417) boosted the effectiveness of radiotherapy in an immune-mediated manner. Using flow cytometry, we found that sonrotoclax combined with radiotherapy polarized tumor-associated macrophages (TAMs) toward the M1-type and promoted the infiltration of Gzmb+ CD8+ T cells into the tumor. Mechanistically, we demonstrated that the combination of sonrotoclax and radiotherapy induced immunogenic ferroptosis of cancer cells by inhibiting GPX4 expression, released tumor-associated damage-associated molecular patterns (DAMPs) and subsequently activated the NF-κB pathway in TAMs. Moreover, the combination therapy also led to aberrant cytosolic DNA abundance and activated the cGAS-STING pathway in cancer cells, leading to the release of type I interferons and enhanced activation of CD8+ T cells. Meanwhile, the activation of cGAS-STING pathway also led to the upregulation of PD-L1 expression. Further combination of sonrotoclax and radiotherapy plus anti-PD-L1 exerted the most significant anti-tumor effects. Overall, our study indicated that sonrotoclax enhanced the anti-tumor immune response of radiotherapy through non-apoptotic roles of BCL-2, and shed light on the further clinical evaluation of the triple combination therapy of sonrotoclax, radiotherapy and immunotherapy.

Chemotherapeutic resistance is a major obstacle to chemotherapeutic failure. Cancer cell resistance involves several mechanisms, including epithelial-to-mesenchymal transition (EMT), signaling pathway bypass, drug efflux activation, and impairment of drug entry. P-glycoproteins (P-gp) are an efflux transporter that pumps chemotherapeutic drugs out of cancer cells, resulting in chemotherapeutic resistance. Several types of long noncoding RNA (lncRNAs) have been identified in resistant cancer cells, including ODRUL, MALAT1, and ANRIL. The high expression level of ODRUL is related to the induction of ATP-binding cassette (ABC) gene expression, resulting in the emergence of doxorubicin resistance in osteosarcoma. lncRNAs are observed to be regulators of drug transporters in cancer cells such as MALAT1 and ANRIL. Targeting P-gp expression using natural products is a new strategy to overcome cancer cell resistance and improve the sensitivity of resistant cells toward chemotherapies. This review validates the inhibitory effects of natural products on P-gp expression and activity using in silico molecular docking. In silico analysis showed that Delphinidin and Asparagoside-f are the most significant natural product inhibitors of p-glycoprotein-1. These inhibitors can reverse multi-drug resistance and induce the sensitivity of resistant cancer cells toward chemotherapy based on in silico molecular docking. It is important to validate that pre-elementary docking can be confirmed using in vitro and in vivo experimental data.

Genotoxic therapies such as ionizing radiation eliminate cancer cells by inducing extensive DNA damage but often cause normal tissue toxicity, including cutaneous injury. Extrachromosomal circular DNA (eccDNA) refers to circular DNA fragments outside the chromosomal context, with their formation and persistence linked to DNA damage repair and genomic instability. Despite growing recognition of eccDNA in oncogenesis, its role under genotoxic stress in normal tissues remains poorly understood. Here, eccDNA is profiled in irradiated rat skin using Circle-seq, identifying alterations in eccDNA number and composition. Specifically, radiation induced circle17:44148731-48208624, in which vacuolar protein sorting 41 homolog (VPS41) is the sole radiation-induced amplification gene by semiquantitative PCR and gel electrophoresis. The findings show that eccDNA or VPS41 overexpression reduces radiation-induced skin injury (RISI) in vitro and in vivo. Proteomic and interaction analyses identified metastasis suppressor kangai-1 (KAI1) as a VPS41-interacting partner. Notably, VPS41 overexpression promotes KAI1 lysosomal degradation, protecting against radiation-induced apoptotic cell death. Peptide array analysis pinpoints the VPS41-KAI1 interaction through the K263 residue, consistent with AlphaFold prediction. The findings uncover a novel mechanism in which radiation-induced eccDNA, specifically VPS41, mitigates skin injury by modulating KAI1 degradation. This study highlights the role of eccDNA in cellular defense, providing strategies to enhance tissue resilience to genotoxic stress.

Chemoresistance and immunosuppression are common obstacles to the efficacy of chemo-immunotherapy in colorectal cancer (CRC) and are regulated by mitochondrial chaperone proteins. Here we show that the disruption of the tumour necrosis factor receptor-associated protein 1 (TRAP1) gene, which encodes a mitochondrial chaperone in tumour cells, causes the translocation of cyclophilin D in tumour cells. This process results in the continuous opening of the mitochondrial permeability transition pore, which enhances chemotherapy-induced cell necrosis and promotes immune responses. On the basis of this discovery we developed an oral CRISPR-Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes that disrupts the TRAP1 gene in CRC. This system penetrates the intestinal mucus layer and undergoes epithelial transcytosis, accumulating in CRC tissues. It enhances chemotherapeutic efficacy by overcoming chemoresistance and activating the tumour immune microenvironment in orthotopic, chemoresistant and spontaneous CRC models, with remarkable synergistic antitumour effects. This oral CRISPR-Cas9 delivery system represents a promising therapeutic strategy for the clinical management of CRC.

Omentum transplantation has emerged as a versatile and effective technique across various surgical disciplines due to its unique properties of immunological surveillance, anti-inflammatory effects, and wound healing promotion. In breast cancer surgeries, it has been utilized to manage locoregional issues and immediate reconstruction, providing satisfactory cosmetic outcomes and minimal complications, particularly in patients who had previously undergone irradiation. For esophageal cancer, omental reinforcement has significantly reduced anastomotic leak rates and postoperative complications, supporting its use in esophagectomy and complex cardiothoracic surgeries. In gynecological surgeries, the use of omental flaps has shown excellent results in neovaginal reconstruction following pelvic exenteration, offering distinct advantages over myocutaneous flaps by reducing morbidity and preserving sexual function. Additionally, omental transposition has proven beneficial in reducing surgical morbidity following radical abdominal hysterectomy and in managing vaginal cuff dehiscence through vaginal approaches. Robotic-assisted omental flap harvesting has enhanced precision and reduced complications in reconstructive surgeries, making it a promising minimally invasive approach in regenerative surgery and complex reconstructions, such as for facial skeleton reconstruction. The omentum has also been beneficial in laparoscopic procedures for pudendal nerve decompression and in managing thoracic aortic graft infections, demonstrating its versatility and effectiveness in various clinical settings. These studies collectively highlight the omentum's significant role in improving surgical outcomes, reducing complications, and enhancing the quality of life for patients, solidifying its place as a valuable tool in modern surgical practice. This article provides a comprehensive narrative review of omentum transplantation in oncology, discussing its current applications and future potential as a standard treatment modality.

Internal radiotherapy holds a greater potential than external radiotherapy for precisely destroying tumors and minimizing side effects. 125I seeds are routinely used as radioactive sources in clinical brachytherapy for patients with various types of cancers. However, 125I seeds are losing ground to flashier cancer therapies, mainly due to their limited therapeutic efficacy, uneven dose distribution, and negligible antitumor immune response. Here, we present porphyrin-engineered 125I-nanoseeds as a prototype for immunogenic brachytherapy. 125I-nanoseeds were rationally designed as a core-shell structure, in which Au@Ag cores enhance the energy deposition of photons to produce more ·OH, while porphyrin shells transfer the energy of Auger electrons to generate 1O2. Benefiting from improving energy utilization efficiency, 125I-nanoseeds can efficiently produce ·OH and 1O2 in tumors, enhancing antitumor efficacy and inducing immunogenic cell death in both murine tumor models and human tumor tissues. When combined with checkpoint blockade immunotherapy, 125I-nanoseeds elicit a systemic immune response in tumor-bearing mice, inhibiting both distant and metastatic tumors. This work demonstrates that porphyrin-engineered 125I-nanoseeds can synergize brachytherapy and dynamic therapy, resulting in enhanced antitumor efficacy and antitumor immune response compared to those of clinical 125I seeds, which is expected to improve the applied prospect of clinical brachytherapy.

Pyroptosis, a programmed cell death mechanism that bypasses apoptosis resistance and triggers tumor-specific immune responses, has gained much attention as a promising approach to cancer therapy. Despite enhancing tumor accumulation and extending the circulation of small-molecule drugs, nanomedicines still face significant challenges, including poor tissue penetration, tumor resistance, and hypoxic microenvironments. To overcome these challenges, a novel near-infrared II (NIR-II) J-aggregate-based nanomedicine is designed, leveraging an in situ secondary self-assembly strategy to fabricate highly targeted nanoparticles (MSDP NPs). These nanomedicines trigger pyroptosis by generating type I reactive oxygen species, especially superoxide anions, while simultaneously activating photoimmunotherapy. In vivo studies demonstrate that MSDP NPs achieve efficient tumor penetration and prolong tumor retention, which is facilitated by the J-aggregate-driven formation of microscale spindle-shaped fibrillar bundles through in situ secondary self-assembly at the tumor site. This unique structural transformation enhances nanomedicine accumulation in tumor tissues, enabling robust NIR-II fluorescence imaging and improving therapeutic efficacy even in hypoxic tumor microenvironments. This study provides an innovative phototheranostic strategy that utilizes the in situ secondary self-assembly of NIR-II J-aggregates to induce tumor pyroptosis, offering a potential solution to the limitations of current nanomedicines in cancer therapy.

Designing advanced biomimetic nanoplatforms that combine photothermal therapy (PTT) and immune activation represents a modern approach to addressing the challenges of cancer therapy. This study presents a nanobiomimetic hollow copper-sulfide (HCuS) platform for precise homotypic tumor targeting and melanoma treatment. The HCuS@OVA@CM (COC) nanoplatform-encapsulated ovalbumin (OVA) antigen protein within HCuS nanoparticles and was coated with melanoma cell membranes (B16F10). Importantly, this design facilitates specific tumor accumulation and achieves 16.0% photothermal conversion efficiency under 1064 nm NIR-II irradiation, which is a key factor for therapeutic success. In vitro studies have demonstrated that this nanoplatform induces immunogenic cell death (ICD), enhances antigen presentation, and stimulates dendritic cell (DCs) maturation. In vivo experiments confirmed that COC-mediated NIR-II photothermal treatment significantly suppressed tumor growth without notable body weight loss. This biomimetic nanoplatform approach offers a targeted, enhanced, and effective immune response for tumor photothermal immunotherapy, making it a promising candidate for advanced melanoma treatment and anticancer therapy.

As a form of inflammation-associated cell death, pyroptosis has gained widespread attention in recent years. Accumulating evidence indicates that pyroptosis regulates tumor growth and is associated with autoimmune disorders and inflammatory response. Paclitaxel, a traditional Chinese medicine, usually induces death of cancer cells as a chemotherapeutic agent. Previous studies have revealed that paclitaxel can exert an anti-tumor effect through a variety of cell death mechanisms, of which pyroptosis plays a pivotal role in inhibiting tumor growth and enhancing anti-tumor immunity. In this review, we summarize the current advances in therapeutic connections between pyroptosis and paclitaxel in anti-tumor effects.