Ring finger protein 125 (RNF125), a ubiquitin E3 ligase, has been reported to act as a tumor suppressor in several cancers, but its precise function in lung adenocarcinoma (LUAD) has not been elucidated. In the present study, through bioinformatics analysis and immunohistochemistry in LUAD and non‑cancerous samples, it was demonstrated that RNF125 was significantly downregulated in lung cancer. Low levels of RNF125 expression were associated with metastatic status, advanced tumor stage and poor overall survival in LUAD. The results of gain‑ and loss‑of‑function experiments demonstrated that RNF125 inhibited proliferation, colony formation, migration and invasion of LUAD cells. In addition, RNF125 increased the sensitivity of LUAD cells to cisplatin. Mechanistically, RNF125 interacted with programmed cell death ligand 1 (PD‑L1) and reduced PD‑L1 expression levels in LUAD cells. Furthermore, IL‑2 secretion by Jurkat T cells was significantly suppressed when co‑cultured with RNF125‑silenced LUAD cells. NK‑92 cell lysis of RNF125‑silenced LUAD cells was also weaker compared with that of control LUAD cells, suggesting that RNF125 knockdown enhanced the immune evasion ability of LUAD cells. Notably, the results of the present study identified that the RNA‑binding protein muscleblind‑like 1 (MBNL1) is the upstream regulator of RNF125 in LUAD. MBNL1 increased the stability of the RNF125 transcript in LUAD cells and knockdown of RNF125 reversed the antitumor effect of MBNL1 on LUAD cells. In conclusion, the present study demonstrated the tumor suppressor role of RNF125 in LUAD and implicated MBNL1 as an upstream regulator of RNF125 in LUAD. These findings contributed to an improved understanding of the molecular features of LUAD progression.

This study aimed to elucidate the underlying mechanisms regarding microRNA-708-5p (miR-708-5p) in lung adenocarcinoma (LUAD). Here, the co-culture system of LUAD cells and macrophages, as well as a xenograft mouse model, were established. High levels of miR-708-5p were observed in LUAD. Exosomal miR-708-5p facilitated M2-like phenotype polarization, whereas miR-708-5p inhibition blocked the polarization. Exosomal miR-708-5p was identified as a pivotal signaling molecule for macrophages to mediate tumor cell proliferation, invasion, migration and IFN-γ production in T cells. In addition, miR708-5p was observed to induce PD-L1 expression, and PD-L1 silencing inhibited macrophage-induced tumor cell growth behavior and regulated CD8 T cell activity. In xenograft models, miR-708-5p inhibition and PD-L1 silencing attenuated macrophage-induced tumor growth, induced IFN-γ secretion and CD8 expression, and modulated the PTEN/AKT/mTOR pathway. In LUAD patients, there was an upregulation of both miR-708-5p and PD-L1 expression, accompanied by the activation of PTEN/AKT/mTOR. In conclusion, this study demonstrated the induction of M2 macrophage polarization and PD-L1 expression by exosomal miR-708-5p. We observed that exosomal miR-708-5p mediated the PTEN/AKT/mTOR pathway, diminished CD8 T cell activity and accelerated LUAD progression. The inhibition of specific exosomal miRNA secretion and anti-PD-L1 in the LUAD microenvironment may represent a promising avenue for LUAD immunotherapy.

Triple-negative breast cancer (TNBC) lacks effective targeted therapies due to absent hormone receptors and HER2 expression, often resulting in poor prognosis. This study developed a theranostic system, AptPD-L1-FSNPs, combining PD-L1 aptamers with fluorescent silica nanoparticles (FSNPs) for targeted imaging and therapy in TNBC.

PD-L1 aptamers were conjugated to FSNPs, forming AptPD-L1-FSNPs. In vitro binding was evaluated using PD-L1-positive TNBC cells and negative controls. In vivo tumor targeting and biodistribution were assessed via fluorescence imaging in TNBC-bearing mice. Therapeutic efficacy was measured by tumor growth inhibition, survival, and apoptosis, with toxicity assessed in major organs.

AptPD-L1-FSNPs showed high specificity to PD-L1-expressing TNBC cells and prolonged tumor retention in vivo. Treatment led to reduced tumor growth, increased apoptosis, and improved survival with minimal toxicity.

AptPD-L1-FSNPs offer targeted TNBC imaging and therapeutic potential, demonstrating promise for future clinical applications in personalized cancer treatment.

While immune checkpoint inhibitors targeting programmed cell death-ligand 1 (PD-L1) demonstrate clinical efficacy in hepatocellular carcinoma (HCC), tumor cells frequently evade immune surveillance through PD-L1 overexpression, a phenomenon whose regulatory mechanisms remain poorly understood. Through integrated analysis of single-cell transcription sequence data, we identified aberrant upregulation of Lamin B2 (LMNB2) specifically in immunotherapy-sensitive HCC patients. Functional characterization revealed that LMNB2 acts as a transcriptional regulator of PD-L1, potentiating immune escape mechanisms in HCC cells during co-culture with Jurkat cells. Notably, we discovered that speckle-type POZ protein (SPOP) directly interacts with LMNB2 to mediate its ubiquitination and proteasomal degradation, thereby maintaining physiological PD-L1 expression levels. Clinically relevant SPOP mutations or reduced SPOP expression impaired this regulatory mechanism, leading to LMNB2 accumulation and subsequent PD-L1 hyperactivation. Importantly, combinatorial targeting of LMNB2 with Atezolizumab (PD-L1 inhibitor) displayed a synergistic effect on suppressing tumor progression both in vitro and in vivo, particularly in HCC models with SPOP mutations or LMNB2 overexpression. These findings unveil a novel ubiquitination-dependent regulatory axis in HCC immune evasion and propose targeted co-inhibition strategies to overcome HCC immunotherapy resistance.

Ferroptosis represents a distinctive and distinct form of regulated cellular death, which is driven by the accumulation of lipid peroxidation. It is distinguished by altered redox lipid metabolism and is linked to a spectrum of cellular activities, including cancer. In breast cancer (BC), with triple negative breast cancer (TNBC) being an iron-and lipid-rich tumor, inducing ferroptosis was thought to be a novel approach to killing breast tumor cells. However, in the recent past, a novel conceptual framework has emerged which posits that in addition to the promotion of tumor cell death, ferritin deposition has a potent immunosuppressive effect on the tumor immune microenvironment (TIME) via the influence on both innate and adaptive immune responses. TIME of BC includes various cell populations from both the innate and adaptive immune systems. In this review, the internal association between iron homeostasis and the progression of ferroptosis, along with the common inducers and protectors of ferroptosis in BC, are discussed in detail. Furthermore, a comprehensive analysis is conducted on the dual role of ferroptosis in immune cells and proto-oncogenic functions, along with an evaluation of the potential applications of immunogenic cell death-targeted immunotherapy in TIME of BC. It is anticipated that our review will inform future research endeavors that seek to integrate ferroptosis and immunotherapy in the management of BC.

The VRK2 ser-thr kinase, belonging to the dark kinome, is implicated in the pathogenesis of cancer progression, neurological and psychiatric diseases. The VRK2 gene codes for two isoforms. The main isoform (VRK2A) is mainly located in the cytoplasm, and anchored to different types of membranes, such as the endoplasmic reticulum, mitochondria and nuclear envelope. The VRK2A isoform interacts with signaling modules assembled on scaffold proteins such as JIP1 or KSR1, forming stable complexes and blocking the activation of regulatory signaling pathways by altering their intracellular localization and the balance among them. VRK2 regulates apoptosis, nuclear membrane organization, immune responses, and Cajal bodies. Wild-type VRK2 is overexpressed in tumors and contributes to cancer development. In cells and tumors with low levels of nuclear VRK1, VRK2 generates by alternative splicing a shorter isoform (VRK2B) that lacks the C-terminal hydrophobic tail and permits its relocation to nuclei. Furthermore, rare VRK2 gene variants are associated with different neurological or psychiatric diseases such as schizophrenia, epilepsy, bipolar disorder, depression, autism, circadian clock alterations and insomnia, but their pathogenic mechanism is unknown. These diseases are a likely consequence of an altered balance among different signaling pathways that are regulated by VRK2.

Immunotherapeutics against triple-negative breast cancer (TNBC) hold great promise. In this work, we provide a combination therapy for simultaneous increasing tumor immunogenicity and down-regulating programmed cell death ligand 1 (PD-L1) to boost antitumor immunity in TNBC. We prepare bis (diethyldithiocarbamate)-copper/indocyanine green nanoparticles (CuET/ICG NPs) simply in aqueous with one-pot method. CuET/ICG NPs interfere mitochondria, reduce oxygen consumption, and alleviate tumor hypoxia to potentiate photodynamic therapy (PDT) for amplifying immunogenic cell death (ICD). Meanwhile, mitochondria dysfunction leads to energy stress and activates AMPK pathway. As a result, CuET/ICG NPs downregulates membrane PD-L1 (mPD-L1) on both 4T1 cancer cells and cancer stem cells (CSCs) through AMP-activated protein kinase (AMPK)-mediated pathway in hypoxia. Cooperatively, the combinational therapy activates antitumor immunity and triggers long lasting immune memory response to resist tumor re-challenge. Our study represents an attempt that conquers tumor immunosuppressive microenvironment with simple biomedical materials and multimodality treatments.

Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.

Tumor immune evasion is a complex and adaptive mechanism that allows cancer cells to escape immune detection and destruction, contributing to malignancy progression and poor therapeutic outcomes. This review article explores the integral role of the let-7 family of microRNAs (miRNAs) in mediating tumor immune evasion, particularly how these regulators influence the tumor microenvironment (TME) and immune cell functionality. The let-7 family, known for its tumor-suppressive roles, modulates key immune checkpoints, including PD-L1, and pathways linked to immune response regulation, such as the STAT3/SOCS axis, impacts macrophage polarization and modulates immune cell function. Dysregulation of let-7 miRNAs can enhance tumor immune evasion through mechanisms such as downregulating major histocompatibility complex (MHC) expressions, promoting immunosuppressive cell populations, and manipulating metabolic pathways, which together establish an immunosuppressive TME. Conversely, specific let-7 members show potential in restoring anti-tumor immunity by reversing immune suppression and improving T cell responses. By synthesizing current research, this article underscores the dual role of let-7 in both promoting and inhibiting tumor immune evasion, suggesting their potential as therapeutic targets and biomarkers in cancer immunotherapy. Future studies on the context-dependent roles and advanced delivery systems for let-7-targeting therapies are crucial for enhancing immunotherapeutic efficacy and improving patient outcomes across malignancies.

Precise modulation of dynamic and complex tumor microenvironment (TME) to disrupt tumorigenesis and reshape intratumoral immune infiltration has emerged as promising approaches for enhanced cancer therapy. Among recent innovations, proteolysis-targeting chimeras (PROTACs) represent a burgeoning chemical knockdown technology capable of degrading oncogenic protein homeostasis and inducing dynamic alternations within carcinoma settings, offering potential for antitumor manipulation. However, achieving selectivity in PROTACs that respond to disease environmental stimulation and precisely perturb on-target proteins remains challenging. The multi-step synthesis and limited permeability, attributed to high-molecular-weight and heterobifunctional structures, further hinder their in vivo efficacy. Herein, we present a unique TME-responsive enzyme-activated clickable PROTACs, which features a short peptide-tagged pomalidomide derivative to undergo tumor-specific cleavage by cathepsin protease to induce orthogonal crosslinking of the exposed cysteine with 2-cyanobenzothiazole-labeled epigenetic protein-ligand JQ1, facilitating in situ degrader formation within tumor regions only. Systematic protein profiling and proteomic analysis revealed that such TME-specific clickable-PROTACs not only selectively eliminate epigenetic proteins without tedious pre-synthesis to bridge disparate small-molecule bi-warhead fragments, but also demonstrated superior tumor penetration compared to conventional high-molecular-weight PROTACs. Importantly, these clickable-PROTACs efficiently downregulated immune checkpoint programmed death-ligand 1 (PD-L1) both in vitro and in vivo, remodeling TME for enhanced therapeutics, especially in anti-tumoral immunomodulation.

Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy worldwide, and represents a major global health challenge. While surgical resection at early stages offers favorable prognosis with 5-year survival rates exceeding 70%, the clinical reality in China reveals a contrasting scenario, where over 60% of patients present with advanced disease, resulting in a dramatic decline in 5-year survival to below 12.5%. The immunological landscape plays a pivotal role in HCC pathogenesis and progression, comprising two complementary arms: the innate immune system's rapid-response mechanism for immediate tumor surveillance and the adaptive immune system's antigen-specific targeting with immunological memory capabilities. Emerging evidence has highlighted ubiquitination, a sophisticated post-translational modification system, as a critical regulator of immune homeostasis in HCC pathogenesis. This molecular process exerts precise control through three primary mechanisms: (1) Modulation of immune cell activation thresholds via proteasomal degradation of signaling proteins, (2) Orchestrating immune cell differentiation through stability regulation of transcriptional factors, and (3) Maintenance of immune tolerance by dynamic modification of checkpoint regulators. Such multifaceted regulation affects both innate immune recognition pathways (e.g., NF-κB and STING signaling) and adaptive immune effectors (particularly T cell receptor signaling cascades). This comprehensive review establishes a threefold Objective: First, to elucidate the mechanistic interplay between ubiquitination networks and HCC-related immune dysregulation; Second, to systematically analyze how innate immune-associated ubiquitination events drive hepatocarcinogenesis through chronic inflammation modulation; and third, to critically evaluate recent clinical advances combining ubiquitination-targeted therapies (e.g., proteasome inhibitors and E3 ligase modulators) with immunotherapeutic regimens. Our synthesis revealed that strategic manipulation of ubiquitination pathways can potentiate PD-1/PD-L1 blockade efficacy while mitigating therapeutic resistance, particularly through modulation of tumor-associated macrophages and exhausted T cell populations. By integrating fundamental mechanistic insights with translational clinical data, this review provides a conceptual framework for the development of next-generation diagnostic biomarkers and rational therapeutic combinations. The proposed strategy of ubiquitination-immune axis modulation holds significant potential to transform current HCC management paradigms, offering new avenues for precision immunotherapy for this challenging malignancy.

Neovascular age-related macular degeneration (NVAMD) is a common retinal disease causing vision loss in the elderly. Neuroinflammation significantly contributes to NVAMD's etiology. This study explores the role of Programmed cell death ligand 1 (PD-L1), an immune checkpoint (ICP) in microglia, known for limiting neuroinflammation in neurodegenerative diseases, and its potential function in NVAMD. This work finds increased PD-L1 expression in retinal microglia following laser injury. PD-L1 knockout (KO) or inhibitory PD-L1 antibody treatment worsens vascular leakage and neoangiogenesis in a laser-induced NVAMD mouse model, effects reversible by microglia depletion with PLX5622. This study underscores that choroidal neovascularization (CNV) may be regulated by multiple mechanisms, with PD-L1 modulation representing one of these pathways. Blocking PD-L1 elevated proinflammatory factors and p-ERK levels, indicating microglial overactivation in NVAMD. Conversely, enhancing PD-L1 signaling reduced neuroinflammation and neovascularization via ERK. These findings highlight PD-L1's role in neoangiogenesis and neuroinflammation in NVAMD, suggesting its potential as a target for immunomodulatory treatment in NVAMD.

Recent research indicates that programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors show promise in treating triple-negative breast cancer (TNBC), but their efficacy is lower than anticipated, especially when used alone. Therefore, enhancing the anti-tumor immune response strategy for TNBC is crucial. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), involved in tumor cell regulation and a potential therapeutic target, has an undefined role in TNBC immunotherapy. In this study, we explored the inverse correlation between UCH-L1 and PD-L1 in TNBC patient tissues. Through in vitro experiments, we found that UCH-L1 negatively regulates PD-L1 by stabilizing the E3 ubiquitin ligase ariadne-1 homolog (ARIH1), which promotes PD-L1 ubiquitination and degradation. Further analysis in Balb/c mice xenograft tumors showed that UCH-L1 correlates with GZMB+/CD8+ T cell infiltration in TNBC, suggesting potential synergistic effects when combining UCH-L1 inhibitors with PD-L1 antibodies. Overall, in TNBC, UCH-L1 stabilizes ARIH1, leading to low PD-L1 expression, which may explain the limited effectiveness of immunotherapy in TNBC patients. Our mouse experiments showed improved therapeutic effects when combining UCH-L1 inhibitors with PD-L1 antibodies. These findings offer a new avenue for immunotherapy in TNBC patients.

Chimeric antigen receptor CAR T cell therapy faces notable limitations in treatment of solid tumors. The suppressive tumor microenvironment TME, characterized by complex interactions among immune and stromal cells, is gaining recognition in conferring resistance to CAR T cell therapy. Despite the abundance and diversity of macrophages in the TME, their intricate involvement in modulating responses to CAR T cell therapies remains poorly understood. Here, we conducted single-cell RNA sequencing scRNA seq on tumors from 41 glioma patients undergoing IL13Ra2-targeted CAR T cell therapy, identifying elevated suppressive SPP1 signatures predominantly in macrophages from patients who were resistant to treatment. Further integrative scRNA seq analysis of high-grade gliomas as well as an interferon-signaling deficient syngeneic mouse model both resistant to CAR T therapy demonstrated the role of congruent suppressive pathways in mediating resistance to CAR T cells and a dominant role for SPP1+ macrophages. SPP1 blockade with an anti-SPP1 antibody abrogates the suppressive TME effects and substantially prolongs survival in IFN signaling-deficient and glioma syngeneic mouse models resistant to CAR T cell therapy. These findings illuminate the role of SPP1+ macrophages in fueling a suppressive TME and driving solid tumor resistance to CAR cell therapies. Targeting SPP1 may serve as a universal strategy to reprogram immune dynamics in solid tumors mitigating resistance to CAR T therapies.

Gastric cancer (GC) is one of the primary contributors to cancer-related mortality on a global scale. It holds a position within the top five most prevalent malignancies both in terms of occurrence and fatality rates. Immunotherapy, as a breakthrough cancer treatment, brings new hope for GC patients. Various biomarkers, such as the expression of programmed death ligand-1 (PD-L1), the microsatellite instability (MSI) status, tumor mutational burden (TMB), and Epstein-Barr virus (EBV) infection, demonstrate potential to predict the effectiveness of immunotherapy in treating GC. Nevertheless, each biomarker has its own limitations, which leads to a significant portion of patients continue to be unresponsive to immunotherapy. With the understanding of the tumor immune microenvironment (TIME), genome sequencing technology, and recent advances in molecular biology, new molecular markers, such as POLE/POLD1mutations, circulating tumor DNA, intestinal flora, lymphocyte activation gene 3 (LAG-3), and lipid metabolism have emerged. This review aims to consolidate clinical evidence to offer a thorough comprehension of the existing and emerging biomarkers. We discuss the mechanisms, prospects of application, and limitations of each biomarker. We anticipate that this review will open avenues for fresh perspectives in the investigation of GC immunotherapy biomarkers and promote the precise choice of treatment modalities for gastric cancer patients, thereby advancing precision immuno-oncology endeavors.

Acute myeloid leukemia (AML) exhibits a pronounced ability to develop drug resistance and undergo disease relapse. Recent research has noticed that resistance to treatments could substantially be attributed to drug-tolerant persister (DTP) cells, which are capable of surviving under therapeutic pressures. These are transient, reversibly dormant cells with the capability to act as a reservoir for disease relapse. DTP cells utilize diverse adaptive strategies to optimize the ecological niche, undergo metabolic reprogramming, and interact with microenvironment. The persister state of AML is established through transient cellular reprogramming, thus allowing cells to survive the initial phase of drug therapy and develop drug resistance. Our review explores the identification and phenotypic characteristics of AML DTP cells, as well as their clinical relevance. We summarize the mechanisms underlying the persistence of AML DTP cells and the molecular attributes that define the DTP state. We further address the current challenges and future prospects of DTP-targeting approaches. Understanding these features may provide critical insights into novel therapeutic strategies aimed at targeting AML DTP cells, especially in the new era of immunotherapy against AML.

The tumor microenvironment (TME) inherently exhibits treatment resistance, which restrains the therapeutic effect. Here, intracellular piezoelectric catalysis and stepwise nitric oxide (NO) release were integrated to modulate the TME for anticancer therapy. A piezoelectric homologous boron nitride (BN) heterostructure (BN3:1) was prepared, which promotes the piezoelectric character and facilitates the spatial separation of ultrasound (US)-generated charges. The electrons dominate reactive oxygen species (ROS) generation, and the holes also consume endogenous glucose and nicotinamide adenine dinucleotide phosphate (NADPH). The simultaneous reactions of electrons and holes not only facilitate charge separation but also disrupt TME metabolism. In addition, BN3:1 releases NO in response to TME-specific H+/H2O2. Under US irradiation, increased ROS generation boosts NO release to damage DNA/mitochondria and decompose the extracellular matrix (ECM). Without US, moderate NO release is conducive to vascular normalization, hypoxia relief, and PD-L1 downregulation. Furthermore, intracellular NO microbubbles amplify US imaging contrast, endowing efficient monitoring of NO release in vitro and in vivo. It is the first time employing BN nanosheets as sonosensitizers and NO donors. The synergistic effect grants great anticancer efficiency, which can also arouse an anticancer immune response to further fight against metastasis and recurrence.

Chemotherapy drug-related acute pancreatitis (CDRAP) is a rare adverse event that poses significant challenges to clinicians. This study aimed to describe plain computed tomography (CT)- and contrast-enhanced computed tomography (CECT)-based conventional imaging features and texture analysis characteristics of CDRAP.

A total of 62 patients with initial clinical and/or biochemical evidence of pancreatitis and 34 patients with normal pancreatic manifestations who underwent CT during chemotherapy were retrospectively included. The diagnosis of CDRAP was established based on clinical, imaging, and biochemical findings. Conventional imaging features, texture analysis characteristics, clinical and biochemical parameters, other complications, chemotherapy drugs, and patient outcomes related to CDRAP were recorded.

A total of 20 (32.26%) patients who were clinically diagnosed with CDRAP had normal pancreatic morphology on CT, while 42 (67.74%) patients presented with changes indicative of acute pancreatitis. The CT findings of 62 CDRAP cases were as follows: diffuse (n = 19) or focal (n = 21) pancreatic enlargement, diffuse (n = 12) or focal (n = 4) heterogeneous enhancement, peripancreatic stranding (n = 20), acute peripancreatic fluid collection (n = 10), and pseudocyst (n = 2). A total of 17 texture features were identified to differentiate CDRAP from normal pancreatic manifestations.

CDRAP mainly manifested as interstitial edematous pancreatitis with/without normal pancreatic morphology on CT. Imaging texture analysis may serve as a potential biomarker for its detection. By combining conventional imaging features with texture analysis characteristics, there is potential to assist radiologists and clinicians in the identification of CDRAP, thereby improving the quality of life for cancer patients.

Copper, an essential micronutrient, plays significant roles in numerous biological functions. Recent studies have identified imbalances in copper homeostasis across various cancers, along with the emergence of cuproptosis, a novel copper-dependent form of cell death that is crucial for tumor suppression and therapeutic resistance. As a result, manipulating copper levels has garnered increasing interest as an innovative approach to cancer therapy. In this review, we first delineate copper homeostasis at both cellular and systemic levels, clarifying copper's protumorigenic and antitumorigenic functions in cancer. We then outline the key milestones and molecular mechanisms of cuproptosis, including both mitochondria-dependent and independent pathways. Next, we explore the roles of cuproptosis in cancer biology, as well as the interactions mediated by cuproptosis between cancer cells and the immune system. We also summarize emerging therapeutic opportunities targeting copper and discuss the clinical associations of cuproptosis-related genes. Finally, we examine potential biomarkers for cuproptosis and put forward the existing challenges and future prospects for leveraging cuproptosis in cancer therapy. Overall, this review enhances our understanding of the molecular mechanisms and therapeutic landscape of copper and cuproptosis in cancer, highlighting the potential of copper- or cuproptosis-based therapies for cancer treatment.

Toll-like receptor 3 (TLR3) is a pattern recognition receptor known to play a crucial role in the immune response to cancer. However, its effect on the efficacy of immunotherapy in lung adenocarcinoma (LUAD) remains unclear. This study aims to investigate the role of TLR3 in LUAD by examining its expression levels, prognostic significance, and impact on immune signaling pathways.

We analyzed the impact of TLR3 expression on the prognosis of lung adenocarcinoma patients using data from the Cancer Genome Atlas (TCGA) database and four additional cohorts (GSE72094, GSE30219, GSE50081 and GSE31210). Functional enrichment analyses were performed to compare molecular features between low and high TLR3 expression groups using gene set variation analysis (GSVA). We also examined the correlation between TLR3 and tumor mutation burden (TMB), immune infiltration, and PD-L1 expression. Further experimental validation was conducted using co-culture systems of LUAD cells and peripheral blood mononuclear cells (PBMCs) with PD1 inhibitors, and Western blot analysis to investigate the involvement of NF-κB signaling.

TLR3 expression was significantly lower in LUAD tissues compared to normal tissues, with high TLR3 expression correlating with better survival outcomes across multiple cohorts. High TLR3 expression was associated with increased TMB and enhanced immune activation. Patients with high TLR3 expression exhibited higher immune checkpoint expression and immune cell infiltration. Experimental results showed that TLR3 agonists increased the susceptibility of LUAD cells to activated PBMCs under PD1 inhibitor therapy, inhibiting cell proliferation, migration, and invasion. Additionally, TLR3 has a strong positive correlation with MHC molecules and upregulated PD-L1 expression. NF-κB was identified as a key regulator of PD-L1 expression, with TLR3 agonists enhancing NF-κB and PD-L1 activity.

TLR3 enhances the anti-tumor immune response in LUAD by modulating NF-κB signaling and PD-L1 expression, making it a promising prognostic biomarker and therapeutic target. This study highlights the potential of TLR3 to improve immunotherapy outcomes, providing a comprehensive analysis of its role in LUAD and paving the way for novel therapeutic strategies targeting TLR3-mediated pathways.

P4HA2 is implicated in regulating tumor microenvironment formation and may play roles in inflammation and tumor immunity. However, its mechanistic involvement in colorectal cancer (CRC) remains largely unexplored.

We analyzed P4HA2 expression in CRC tissues and correlated it with clinicopathological features. Functional assays (CCK8, wound healing, Transwell) were performed to assess proliferation and migration. Proteomic analysis identified downstream targets, with STAT1/PD-L1 pathway validation.

High P4HA2 expression correlated with advanced T/M stages and served as an independent poor prognostic factor. Functional experiments confirmed P4HA2's role in promoting CRC proliferation and migration. Mechanistically, P4HA2 bound to and downregulated STAT1, subsequently modulating the STAT1/PD-L1 pathway.

Our findings reveal P4HA2 promotes CRC progression and suppresses anti-tumor immunity via STAT1/PD-L1 axis regulation. This study uncovers a novel pathogenic mechanism, positioning P4HA2 as a potential therapeutic target in CRC.

Immunotherapy using immune checkpoint inhibitors (ICIs) has become a prominent strategy for cancer treatment over the past ten years. However, the efficacy of ICIs remains limited, with certain cancers exhibiting resistance to these therapeutic approaches. Consequently, several immune checkpoint proteins are presently being thoroughly screened and assessed in both preclinical and clinical studies. Among these candidates, T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is considered a promising target. TIM-3 exhibits multiple immunosuppressive effects on various types of immune cells. Given its differential expression levels at distinct stages of T cell dysfunction in the tumor microenvironment (TME), TIM-3, along with programmed cell death protein 1 (PD-1), serves as indicators of T cell exhaustion. Moreover, it is crucial to carefully evaluate the impact of TIM-3 and PD-1 expression in cancer cells on the efficacy of immunotherapy. To increase the effectiveness of anti-TIM-3 and anti-PD-1 therapies, it is proposed to combine the inhibition of TIM-3, PD-1, and programmed death-ligand 1 (PD-L1). The efficacy of TIM-3 inhibition in conjunction with PD-1/PD-L1 inhibitors is being evaluated in a number of ongoing clinical trials for patients with various cancers. This study systematically investigates the fundamental biology of TIM-3 and PD-1, as well as the detailed mechanisms through which TIM-3 and PD-1/PD-L1 axis contribute to cancer immune evasion. Additionally, this article provides a thorough analysis of ongoing clinical trials evaluating the synergistic effects of combining PD-1/PD-L1 and TIM-3 inhibitors in anti-cancer treatment, along with an overview of the current status of TIM-3 and PD-1 antibodies.

Anti-PD-L1 antibody confers anti-tumor effects, but its long-term use can provoke resistance and adverse effects. Asiaticoside, a bioactive triterpene glycoside from Centella asiatica L., regulates immune function and induces apoptosis of hepatocellular carcinoma (HCC) cells. T cells play a vital role in killing tumor cells and require lymphocyte-specific protein tyrosine kinase (LCK) for activation. Here, we examined whether a combined asiaticoside and anti-PD-L1 treatment regulates T cells via LCK activation to enhance the anti-tumor effect in vivo. We established a subcutaneous mouse HCC model using Hepa1-6 cells and measured spleen and tumor weight. Morphological changes of tumor tissues were assessed by hematoxylin-eosin staining. Tumor cell apoptosis and proliferation were determined by TUNEL staining and KI67 immunohistochemistry. The proportion of activated T cells in the spleen was detected by flow cytometry, and the levels of phosphorylated p-LCK and p-AKT in the spleen were determined by Western blotting. Changes in the levels of serum inflammatory factors were detected with ELISA. Our results revealed that the combined asiaticoside and anti-PD-L1 treatment inhibited tumor growth by enhancing apoptosis and reducing tumor cell proliferation. The treatment activated T cells to increase the proportion of effector T cells in the spleen, evidenced by upregulated p-LCK and p-AKT levels. It also increased the level of TNF-α in the serum and decreased IL-6, implying an enhanced immune response. In conclusion, the combined asiaticoside and anti-PD-L1 treatment enhances the anti-HCC effect in vivo by promoting LCK activation to regulate T cells.

The multifaceted roles and mechanisms of necroptosis in cancer cells remain incompletely understood. Here, we demonstrate that FGFR2 inhibition potently inhibits esophageal squamous cell carcinoma (ESCC) by inducing necroptosis in a RIP1/MLKL-dependent manner and show RIP3 is dispensable in this pathway. Notably, MST1 is identified as a necroptotic pathway component that interacts with RIP1 and MLKL to promote necroptosis by phosphorylating MLKL at Thr216. Additionally, FGFR2 inhibition induces Ser518 phosphorylation and triggers ubiquitin-mediated degradation of NF2, culminating in Hippo pathway suppression. Subsequently, YAP activation promotes RIP1 and MLKL transcriptional upregulation, further amplifying necroptosis. Intriguingly, IL-8 derived from necrotic cells stimulates peripheral surviving tumor cells to increase PD-L1 expression. Dual blockade of FGFR2/PD-L1 or FGFR2/IL-8-CXCR1/2 robustly impedes tumor growth in humanized mouse xenografts. Collectively, our findings delineate an alternative FGFR2-NF2-YAP signaling-dependent necroptotic pathway and shed light on the immunoregulatory role of FGFR2, offering promising avenues for combinatorial therapeutic strategies in clinical cancer management.

Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.

Chronic obstructive pulmonary disease (COPD) and lung cancer are associated diseases. COPD confers a negative prognosis in NSCLC, but the clinical benefit of immune checkpoint inhibitors (ICI) in this population is unclear. A population-level analysis of patients in Ontario, Canada was performed through the ICES (formerly known as the Institute for Clinical Evaluative Sciences) administrative database. Patients with NSCLC and treated with PD-1/PD-L1 immune checkpoint inhibitors between Jan 2010 and Dec 2020 were included. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using Cox proportional hazards regression. Hospitalizations and duration of treatment were compared secondarily using logistic and linear regression. A total of 4306 patients received ICI and 54% of patients had a diagnosis of COPD. Median (95% CI) OS was 9.2 (8.5-9.9) months for patients with COPD and 8.2 (7.3-8.8) for patients without COPD, which was not significantly different (adjusted hazard ratio (aHR) = 0.94, 95% CI, 0.87-1.01, P = 0.092). Similarly, the median time on treatment was not different (85 vs. 99 days, multivariable P = 0.10). However, the 90-day hospitalization rate was decreased in the COPD population (multivariable odds ratio 0.76, 95% CI 0.62-0.94, P = 0.011). Among patients with NSCLC receiving ICI, our data suggest that a diagnosis of COPD does not result in shortened treatment, poorer survival, or higher rates of hospitalization. COPD itself should not be considered a contraindication to ICI.

New treatment strategies are urgently needed for patients with advanced cervical cancer (CC). Here, a synergistic anti-CC effect of a novel combinatorial immunotherapy with adoptively transferred autologous Vγ9Vδ2 T cells and αβ T cells is shown. The pivotal role of both circulating and tumor-infiltrating Vγ9Vδ2 T cells in anti-CC immunity is uncovered. Importantly, autologous Vγ9Vδ2 T cells show a synergistic anti-CC effect with αβ T cells not only through killing tumor directly, but also by promoting the activation and tumoricidal activity of syngeneic αβ T cells through antigen presentation, which can be further boosted by conventional chemotherapy. Moreover, Vγ9Vδ2 T cells can restore the tumoricidal function of αβ T cell through competitively binding to BTN3A1, a TCR-Vγ9Vδ2 ligand on CC cells upregulated by IFN-γ derived from activated αβ T cell. These findings uncover a critical synergistic effect of autologous Vγ9Vδ2 T cells and αβ T cells in immunotherapy of CC and reveal the underlying mechanisms.

Acute myeloid leukemia (AML) is a malignant tumor of blood cells, which seriously interferes with the generation of normal cells. Although miR-186-5p is diminished in AML, its exact mechanism is not well understood. miR-186-5p and PD-L1 levels in AML cells (HL-60, KG-1, TF-1a, MOLT-3) and subcutaneous tumor tissue were discovered through qRT-PCR and Western blot. miR-186-5 p and PD-L1 combining sites were foreseen by the database and verified by dual luciferase and immunoprecipitation experiments. AML cells with miR-186-5p overexpression or knockdown and PD-L1 overexpression were cocultured with CD4+ and CD8+ T cells. The proliferation, migration, invasion and apoptosis of AML cells, CD8+ and CD4+ T cell growth and apoptosis, and activated markers (Perforin and Granzyme B) and secreted cytokines (IFN-γ, IL-4 and TNF-α) levels were detected by CCK8, Transwell, flow cytometry, CFSE, Western blot and ELISA, respectively. Subcutaneous xenograft magnitude and mass in nude mice were measured. Ki67 level was identified through immunohistochemistry. CD4+ and CD8+ T cell level and infiltration were detected by immunofluorescence and flow cytometry. miR-186-5p was downregulated, and PD-L1 was boosted in AML cells and subcutaneous tumor tissues (p < 0.05), while miR-186-5p targeted down-regulate PD-L1. miR-186-5p upregulation hindered AML cell multiplication, migration, invasion and facilitate cell death, and enhanced the proliferation activity, activation markers (Perforin and Granzyme B) and secreted cytokines (IFN-γ, IL-4, TNF-α) of CD8+ and CD4+ T cells, inhibited apoptosis, and inhibited immune escape (p < 0.05). Knockdown of miR-186-5p can promote AML progression, but PD-L1 upregulation weakens the antitumor impact of miR-186-5p overexpression (p < 0.05). Transplanted tumor mice experiments also found that miR-186-5p hindered PD-L1 and tumor growth (p < 0.05). In conclusion, miR-186-5p can target inhibit PD-L1, suppress AML cells multiplication, movement, invasion and immune escape, and then reduce AML, aiming to provide support and basis for the pathological mechanism and prevention and treatment strategy of AML.

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with gastrectomy being the primary treatment option. Sepsis, a systemic inflammatory response to infection, may influence tumor growth by creating an immunosuppressive environment conducive to cancer cell proliferation and metastasis. Here, the effect of abdominal infection on tumor growth and metastasis was investigated through the implementation of a peritoneal metastasis model and a subcutaneous tumor model. In a murine model induced by cecal ligation and puncture (CLP) to simulate the effects of sepsis, we observed significant immune dysregulation, including T-cell exhaustion and the release of myeloid-derived suppressor cells (MDSCs). This immune alteration was associated with increased programmed cell death protein 1 (PD-1) expression on T cells and programmed cell death 1 ligand 1 (PD-L1) expression on MDSCs within the tumor microenvironment, fostering an immune-suppressive environment. Polymorphonuclear MDSCs (PMN-MDSCs) expressing elevated PD-L1 after sepsis demonstrated more substantial suppressive effects on T-cell proliferation than controls. Treatment with anti-PD-1 monoclonal antibodies successfully restored T-cell function, reduced mortality, and decreased metastasis in CLP mice. These findings emphasize the impact of sepsis on tumor progression and suggest targeting the PD-1/PD-L1 axis as a potential therapeutic strategy for managing immune dysfunction in patients with cancer.

Multiple myeloma (MM) is a plasma cell-derived malignancy. While immune checkpoint blockade immunotherapy has advanced myeloma treatment, chemotherapy remains the primary therapy. How chemotherapy interacts with immune checkpoint expression and impacts immunotherapy efficacy remains unclear. Here it is discovered that chemotherapeutic drugs induce DNA damage and activate the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. This activation promotes phosphorylation of the interferon regulatory factor 7 (IRF7), which binds to the promoter region of SERTA-containing domain 1 (SERTAD1, also called SEI1) gene to enhance its transcription. The SEI1 directly interacts with the enhancer factors CREB-binding protein (CBP)/p300 and RNA polymerase II (pol II)-associated factor 1 (PAF1) complex, promoting transcriptional activity and leading to upregulation of programmed death ligand-1 (PD-L1) and immune escape in myeloma. Both in vitro and in vivo experiments demonstrate that treating myeloma cells with PD-L1 antibodies post-chemotherapy significantly enhances the killing efficiency of activated T cells, compared to sequential treatment with chemotherapy and PD-L1 antibodies. This research not only uncovers a pivotal regulatory mechanism of PD-L1 upregulation but also provides a compelling rationale for the integration of chemotherapy and immunotherapy in myeloma treatment.

The cellular uptake and tissue dispersion efficiency of nanomedicines are crucial for realizing their biological functionality. As a cutting-edge category of nanomedicine, covalent organic frameworks (COFs)-based photosensitizers, have been extensively employed in cancer phototherapy in recent years. However, the inherent aggregation tendency of COFs hinders their uptake by tumor cells and dispersion within tumor tissues, thereby limiting their therapeutic efficacy. In this study, we employed Fusobacterium nucleatum (F.n.), a prevalent intratumoral bacterium, to construct a bacterium membrane-wrapped COF, COF-306@FM, which is readily taken up by cancer cells and uniformly dispersed within tumor tissues. Meanwhile, the F.n. membrane can also serve as an immune adjuvant to warm up the "cold" tumor immune microenvironment by enhancing the CD8+ T and B cells infiltration, and inducing the formation of tumor-located tertiary lymphoid structures. Consequently, the response rate of αPD-L1 immunotherapy was drastically promoted to efficiently prevent tumor metastasis and recurrence, causing 84.6 % distant tumor inhibition and complete suppression of tumor metastasis. In summary, this innovative approach not only enhances the therapeutic potential of COFs but also opens up new avenues for integrating microbial and nanotechnological strategies in cancer treatment.

Colorectal cancer (CRC) is a prevalent and highly malignant tumor with a limited response to immune checkpoint inhibitor-based immunotherapy. There is an urgent need for novel immunomodulatory agents to enhance the immunotherapeutic response in CRC. Hedyotis diffusa, known for its immunomodulatory properties, has long been utilized as an adjunct in cancer treatment, positioning it as a potential source for discovering new tumor immunomodulators. In this study, we identified a polysaccharide derived from Hedyotis diffusa (HDP), comprising six monosaccharides: rhamnose, arabinose, galactose, glucose, xylose, and mannose. When combined with PD-1 and CTLA-4 inhibitors, HDP can boost systemic immunity in mice to enhance the effectiveness of immune checkpoint inhibitors in CRC therapy. HDP significantly increases the infiltration of CD4+ and CD8+ T cells into tumor microenvironment and upregulates the expression of key effector molecules derived from cytotoxic T cells. Mechanistic studies reveal that HDP activates the IL-2/IL-2R axis by upregulating IL-2 production and the expression of IL-2 receptor subunits, thereby promoting T cell proliferation. Collectively, this research introduces an innovative strategy to improve the efficacy of tumor immunotherapy by harnessing the immunomodulatory potential of polysaccharides. It also directs a roadmap for developing HDP as a promising immunomodulator for CRC treatment.

The cornerstone of first-line treatment in extensive-stage small cell lung cancer (ES-SCLC) is platinum- and etoposide-based chemotherapy. Platinum compounds could immunomodulate the tumor microenvironment in addition to their cytotoxic effect. Genetic variation in immune checkpoint (IC) pathways may predict chemotherapy efficacy. Polymorphisms in the IC genes were determined, and their association with survival was analyzed in 78 patients with ES-SCLC treated with chemotherapy. PD-L1 protein expression in tumor tissue was determined. Three variants in CD274 were associated with better median progression-free survival (mPFS): rs2297136 (hazard ratio [HR] 0.52, 95% CI 0.29-0.93; p = 0.03), rs2282055 (HR 0.23, 95% CI 0.09-0.64; p = 0.005), and rs822336 (HR 0.41, 95% CI 0.23-0.73; p = 0.002). CTLA4 rs231775 was also associated with mPFS (HR 0.30, 95% CI 0.14-0.63; p = 0.002). The variants CD274 rs2297136 and CD274 rs822336 were associated with platinum sensitivity (odds ratio [OR] 0.13, 95% CI 0.02-0.70; p = 0.02, and OR 0.08, 95% CI 0.01-0.46; p = 0.005, respectively). CD274 rs2297136 was also associated with better overall survival (p = 0.02), but not after adjustment for covariates. No association was found between CD274 germline variants and PD-L1 tumor expression. Our results suggest that CD274 and CTLA4 variants may be predictive biomarkers for platinum plus etoposide treatment in ES-SCLC.

Bladder cancer (BC) in the urinary system remains one of the most prevalent malignancies with high recurrence rate globally. Current treatment schemes against BC such as surgery, chemotherapy, and radiotherapy have substantial limitations including side effects, drug resistance, and poor tumor targeting. Considering the above-mentioned challenges, nanotechnology has become a current research hotspot, particularly liposome-based drug delivery systems, which offer promising novel therapeutic strategies aimed at reducing systemic toxicity, overcoming drug resistance, and enhancing drug targeting. This review systematically elaborates the current research progress on liposomal drug delivery systems in BC treatment, focusing on their application in chemotherapy, immunotherapy, and gene therapy. Additionally, we provide a comprehensive assessment of the benefits and limitations of liposome nanocarriers used in BC treatment. The advanced targeting strategies and combination treatments via liposomal therapies are also discussed, demonstrating that liposomal formulations have great potential application value in the treatment of BC owing to their superior bioavailability, stability, and targeting and minimal adverse effects.

In response to stress stimuli, cells have evolved various mechanisms to integrate internal and external signals to achieve dynamic homeostasis. Lysine acetyltransferase (KATs) and deacetyltransferase (KDACs) are the key modulators of epigenetic modifications, enabling cells to modulate cellular responses through the acetylation and deacetylation of both histone and nonhistone proteins. Understanding the signaling pathways involved in cellular stress response, along with the roles of KATs and KDACs may pave the way for the development of novel therapeutic strategies. This review discusses the molecular mechanisms of acetylation and deacetylation in stress responses related to tumorigenesis, viral and bacterial infections. In tumorigenesis section, we focused on the tumor cells' intrinsic and external molecules and signaling pathways regulated by acetylation and deacetylation modification. In viral and bacterial infections, we summarized the update research on acetylation and deacetylation modification in viral and bacterial infections, which systematical introduction on this topic is not too much. Additionally, we provide an overview of current therapeutic interventions and clinical trials involving KAT and KDAC inhibitors in the treatment of cancer, as well as viral and bacterial infection-related diseases.

The introduction of immunotherapy and target therapy into clinical practice has become a chance for many patients with cancer to prolong their survival while maintaining optimal quality of life. Treatment of lung cancer is excellent evidence of the progress of medical therapies. An understanding of the mechanisms of tumor development has led to the evolution of new methods of treatment. Immunoreceptors of T cells with the immunoglobulin domain ITIM, TIM-3 (T-cell immunoglobulin- and mucin domain-3-containing molecule 3), and LAG-3 (lymphocyte activation gene-3) represent new interesting therapeutic targets. The combination of anti-PD-1 and anti-CTLA-4 blockade has proven the possibility of strengthening the anti-tumor response by acting via two separate mechanisms. Adding additional checkpoints to the PD-1 blockade offers hope for further improvements in the effects of the treatment of patients and expanding the group responding to immunotherapy. This paper presents new promising molecular targets along with studies demonstrating the treatment results using them.

The aim of this study was to investigate the function and regulatory mechanism of Interleukin-6 (IL-6) in pituitary-derived folliculostellate (PDFS) cells and to explore the mechanism of metformin against PDFS cells growth through IL-6.

Immunohistochemical staining was conducted on clinical samples from non-functioning pituitary adenomas (NFPA) patients and normal individuals to assess IL-6 and Programmed Death-Ligand 1(PD-L1) expression. PDFS cells were treated with IL-6 to evaluate their effects on cell viability, proliferation, and migration through various assays. Similar assays were performed to assess the counteractive effects of metformin, focusing on the IL-6/ERK pathway and PD-L1 expression. Western blot analysis was utilized to examine apoptosis-related proteins, and Annexin V-FITC/PI double staining was used to detect cell apoptosis. It also involves assessing the effects of metformin treatment on tumor IL-6 and PD-L1 expression, tumor size, and potential toxic side effects in PDFS xenograft mice.

Clinical samples showed increased IL-6 and PD-L1 expression in NFPA compared to normal pituitary tissues. IL-6 treatment significantly enhanced PDFS cell viability(Increased by 46% within 48 h), proliferation(Increased by 24% within 48 h), and migration(Increased by 19% within 48 h). Metformin treatment resulted in the downregulation of IL-6 expression and mitigated IL-6-induced effects on PDFS cells. Additionally, metformin-induced apoptosis and reduced tumor size in xenograft nude mice without observable toxic side effects.

Metformin downregulates the expression of IL-6 in PDFS cells, inhibits the activation of the ERK pathway, thereby suppressing cell proliferation and PD-L1 expression, and induces cell apoptosis.