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.

Background: The cyclic GMP-AMP synthase (cGAS)-type I interferon (IFN-I) pathway detects cytoplasmic DNA and triggers immune responses. Cancer cells often suppress this pathway to evade immune surveillance; however, its therapeutic potential remains unclear. Methods: Mouse oral squamous cell carcinoma models, representing a prominent subtype of head and neck squamous cell carcinoma (HNSCC), were employed in this study. Flow cytometry, Western blot, ELISA, and PCR were used for analysis. Results: We found that immune-unresponsive MOC2 tumors exhibited a deficiency of antigen-presenting cells and cytotoxic T lymphocytes, along with a significant suppression of the cGAS-IFN-I pathway, compared to immune-responsive MOC1 tumors. An MOC2-conditioned medium impaired the differentiation of bone marrow-derived cells into dendritic cells (DCs), reducing the expression of DC markers as well as class I and II major histocompatibility complex (MHC) molecules. The activation of the cGAS-IFN-I pathway in MOC2 cells, either through exogenous DNA or direct IFN-I expression, enhanced class I MHC expression and antigen presentation on MOC2 cells. Furthermore, IFNB1 expression in MOC2 cells induced apoptosis and upregulated chemokines, such as CXCL9 and CXCL10, which recruit immune cells. In immunocompetent mice, IFNB1 expression suppressed MOC2 tumor growth by attracting DCs and T cells, an effect amplified by co-expressing the granulocyte-macrophage colony-stimulating factor. Conclusions: These findings highlight the potential of enhancing cancer cell-intrinsic cGAS-IFN-I signaling to improve tumor immune surveillance and control the progression of immune-cold HNSCC tumors.

Conventional dendritic cell and plasmacytoid dendritic cell (pDC) subsets have specialized functions that can be modulated by the tumor microenvironment, and produce different interferons that are central to antitumor immune responses. While the function of type I interferons in tumor immunity is well characterized, that of type III interferons produced by type 1 conventional dendritic cells in the tumor microenvironment remains unclear. Here we demonstrate in vitro that type III interferons orchestrate pDC survival, activation and TLR7 expression in the blood, thereby enhancing pDC responses to a TLR7 ligand. Moreover, we show that tumor-associated pDCs express the highest level of IFNLR1, and that these immune cell subsets are the most responsive to IFN-III. Importantly, type III interferons prevent the inhibition of pDCs induced by TGF-β or PGE2 in tumor soluble milieu from patients to restores production of IFN-α in pDCs. With TGF-β or PGE2 having pleotropic functions in immune regulation, our results thus implicate IFN-III-mediated immune modulation to have broad impact on various pathological situations.

Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such as acute respiratory distress syndrome, sepsis, trauma and ischemia lead to the aberrant cytosolic accumulation and massive release of nucleic acids that are detected by antiviral innate immune receptors in the endosome or cytosol. Activation of receptors for deoxyribonucleic acids and ribonucleic acids triggers inflammation, a major contributor to morbidity and mortality in critically ill patients. In the past decade, there has been growing recognition of the therapeutic potential of targeting nucleic acid sensing in critical care. This review summarizes current knowledge of nucleic acid sensing in acute respiratory distress syndrome, sepsis, trauma and ischemia. Given the extensive research on nucleic acid sensing in common pathological conditions like cancer, autoimmune disorders, metabolic disorders and aging, we provide a comprehensive summary of nucleic acid sensing beyond critical illness to offer insights that may inform its role in critical conditions. Additionally, we discuss potential therapeutic strategies that specifically target nucleic acid sensing. By examining nucleic acid sources, sensor activation and function, as well as the impact of regulating these pathways across various acute diseases, we highlight the driving role of nucleic acid sensing in critical illness.

Tumor-associated macrophages (TAM) are a heterogeneous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment. In this study, we unveiled a mechanism by which scavenger receptor cluster of differentiation 36 (CD36) suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I IFN (IFNI) production, mirroring the inverse correlation between CD36 and IFNI response observed in patients with cancer. IFNI, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFNI signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacologic inhibition of CD36 to rejuvenate antitumor immunity. Significance: CD36 in tumor-associated macrophages mediates immunosuppression and can be targeted as a therapeutic avenue for stimulating interferon production and increasing the efficacy of immunotherapy.

IFNs play a critical role in cancer biology, including impacting tumor cell behavior and instructing the tumor microenvironment (TME). IFNs recently have been shown to reprogram tumor metabolism through distinct mechanisms. Furthermore, IFNs shape the TME by modulating immune cell infiltration and function, contributing to the intricate interaction between the tumor and stromal cells. This review summarizes the effects of IFNs on metabolic reprogramming and their impacts on the function of immune cells within the TME, with a particular focus on the dual roles of IFNs in mediating both anti-tumor and pro-tumor immune responses. Understanding the significance of IFNs-mediated processes aids to advise future therapeutic strategies in cancer treatment.

Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-γ, have been clearly linked to anti-tumor immunity, while others, such as the innate inflammatory cytokines, promote oncogenesis. Here we provide an overview of the functional roles of cytokines in the tumor microenvironment. Although we have a sophisticated understanding of cytokine networks, therapeutically targeting cytokine pathways in cancer has been challenging. We discuss current progress in cytokine blockade, cytokine-based therapies, and engineered cytokine therapeutics as emerging cancer treatments of interest.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors in the world, and its occurrence and development are closely related to the complex immune regulatory mechanisms. As the first barrier of the body's defense, innate immunity plays a key role in tumor immune surveillance and anti-tumor response, in which type I/III interferon (IFN) is an important mediator with significant antiviral and anti-tumor functions. 5-methylcytosine (m5C) modification of RNA is a key epigenetic regulation that promotes the expression of CRC oncogenes and immune-related genes. It can enhance the proliferation, migration, and invasion of tumor cells by affecting mRNA stability, translation efficiency, and nuclear export. In addition, m5C modification modulates the activity of innate immune signaling pathways and inhibits interferon production and function, further helping tumor cells evade immune surveillance. However, there are insufficient elucidations on the interaction between m5C modification and innate immunity in CRC. In this study, the mechanism of interferon I/III in colorectal cancer was systematically reviewed and explored. This work focused on how m5C modification promotes tumor immune escape by affecting the interferon signaling pathway, thereby providing new diagnostic markers and therapeutic targets for clinical use, and enhancing the immunotherapy efficacy.

Extrachromosomal circular DNA (eccDNA), a chromosome-independent circular DNA, has garnered significant attention due to its widespread distribution and intricate biogenesis in carcinoma. Existing research findings propose that multiple eccDNAs contribute to drug resistance in cancer treatments through complex and interrelated regulatory mechanisms. The unique structure and genetic properties of eccDNA increase tumor heterogeneity. This increased diversity is a result of eccDNA's ability to stimulate oncogene remodeling and participate in anomalous splicing processes through chimeric cyclization and the reintegration of loop DNA back into the linear genome. Such actions promote oncogene amplification and silencing. eccDNA orchestrates protein interactions and modulates protein degradation by acting as a regulatory messenger. Moreover, it plays a pivotal role in modeling the tumor microenvironment and intensifying the stemness characteristics of tumor cells. This review presented detailed information about the biogenesis, distinguishing features, and functions of eccDNA, emphasized the role and mechanisms of eccDNA during cancer treatment, and further proposed the great potential of eccDNA in inspiring novel strategies for precision cancer therapy and facilitating the discovery of prognostic biomarkers for cancer.

Neutrophils have a pivotal role in safeguarding the host against pathogens and facilitating tissue remodeling. They possess a large array of tools essential for executing these functions. Neutrophils have a critical role in cancer, where they are largely associated with negative clinical outcome and resistance to therapy. However, the specific role of neutrophils in cancer is complex and controversial, owing to their high functional diversity and acute sensitivity to the microenvironment. In this Perspective, we discuss the accumulated evidence that suggests that the functional diversity of neutrophils can be ascribed to two principal functional states, each with distinct characteristics: classically activated neutrophils and pathologically activated immunosuppressive myeloid-derived suppressor cells. We discuss how the antimicrobial factors in neutrophils can contribute to tumor progression and the fundamental mechanisms that govern the pathologically activated myeloid-derived suppressor cells. These functional states play divergent roles in cancer and thus require separate consideration in therapeutic targeting.

Therapeutic inhibition of programmed cell death ligand (PD-L1) is linked to alterations in interferon (IFN) signaling. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined IFN-related secretory changes in tumor cells following resistance to PD-L1 inhibition. Here we report an anti-PD-L1 treatment-induced secretome (PTIS) in tumor models of acquired resistance that is regulated by type I IFNs. These secretory changes can suppress activation of T cells ex vivo while diminishing tumor cell cytotoxicity, revealing that tumor-intrinsic treatment adaptations can exert broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth can slow or stop when PTIS components are disrupted individually, or when type I IFN signaling machinery is blocked. Interestingly, genetic and therapeutic disruption of PD-L1 in vitro can only partially recapitulate the PTIS phenotype highlighting the importance of developing in vivo-based resistance models to more faithfully mimic clinically-relevant treatment failure. Together, this study shows acquired resistance to immune-checkpoint inhibitors 'rewires' tumor secretory programs controlled by type I IFNs that, in turn, can protect from immune cell attack.

Ovarian cancer (OV) remains the most lethal gynecological malignancy, underscoring the critical need for robust prognostic biomarkers to enhance patient outcomes. In this study, we classified OV patients by their interferon-stimulated gene (ISG) expression profiles and investigated the associations between these subtypes, the immune microenvironment, and survival outcomes.

We employed consensus clustering in the TCGA-OV cohort (n = 376) to classify patients into ISG-related subgroups. Survival analysis, differential gene expression (DESeq), KEGG and GSEA pathway enrichment analyses, genomic variation assessments, immune cell profiling using the CIBERSORT algorithm, and TIDE analysis were conducted in the TCGA-OV cohort. In addition, immune checkpoint marker expressions were assessed using data from the TCGA-OV cohort and multiplex immunofluorescence (mIF) staining on an independent cohort (n = 80).

Two distinct ISG subtypes were identified: ISG Cluster A and ISG Cluster B. Patients in ISG Cluster B exhibited significantly improved overall survival (OS) (p = 0.0442). A total of 328 dysregulated genes were identified, with Cluster B showing overexpression of immune-related genes and enhanced involvement in immune signaling pathways. ISG Cluster B also presented higher tumor mutation burden (TMB) and an enriched immune profile, including M1 macrophages and CD8 + T cells. TIDE analysis indicated a more favorable response to immune checkpoint inhibitors in this cluster, corroborated by high expressions of PD-L1 and ISG15, which were associated with prolonged OS.

Our findings demonstrate that ISG-related subtypes are significantly associated with the immune microenvironment and survival outcomes in OV. The biomarkers identified in this study have the potential to inform precision therapy development, thereby enhancing treatment efficacy and personalized care for OV patients.

Cytokines are the crucial signaling proteins that mediate the crosstalks between the cells of tumor microenvironment (TME). Interferon-1 (IFN-1) are the important cytokines that are widely known for their tumor suppressive roles comprising of cancer cell intrinsic and extrinsic mechanisms. Despite having known antitumor effects, IFN-1 are also reported to have tumor promoting functions under varying circumstances. This dichotomy in the functions of IFN-1 is largely attributed to the acute and chronic activation of IFN-1 signaling in TME. The chronic activation of IFN-1 signaling in tumor cells results in altered stimulation of downstream pathways that result in the expression of tumor promoting proteins, while the acute IFN-1 signaling activation maintains its tumor inhibiting functions. In the present review, we have discussed the anti- and pro-tumor actions of IFN-1 signaling under acute and chronic IFN-1 signaling activation. We have also discussed the downstream changes in signaling components that result in tumor supportive functions of a constitutive IFN-1 signaling. We have further discussed the possible strategies to overcome the detrimental effects of chronic IFN-1 pathway activation and to successfully employ IFN-1 for their beneficial anti-tumor effects.

The gut microbiome has emerged as a crucial player in modulating cancer therapies, including radiotherapy. In the case of breast cancer, the interplay between the microbiome and radiotherapy-derived metabolites may enhance therapeutic outcomes and minimize adverse effects. In this review, we explore the bidirectional relationship between the gut microbiome and breast cancer. We explain how gut microbiome composition influences cancer progression and treatment response, and how breast cancer and its treatments influence microbiome composition. A dual role for radiotherapy-derived metabolites is explored in this article, highlighting both their therapeutic benefits and potential hazards. By integrating genomics, metabolomics, and bioinformatics tools, we present a comprehensive overview of these interactions. The study provides real-world insight through case studies and clinical trials, while therapeutic innovations such as probiotics, and dietary interventions are examined for their potential to modulate the microbiome and enhance treatment effectiveness. Moreover, ethical considerations and patient perspectives are discussed, ensuring a comprehensive understanding of the subject. Towards revolutionizing treatment strategies and improving patient outcomes, the review concludes with future research directions. It also envisions integrating microbiome and metabolite research into personalized breast cancer therapy.

The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)-mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)-GSK3β (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert "cold" tumors to "hot" and to overcome ICI resistance in CRC with KRAS mutations.

Oncolytic viruses (OVs) are promising cancer immunotherapy agents that stimulate anti-tumor immunity through the preferential infection and killing of tumor cells. OVs are currently under limited clinical usage, due in part to their restricted efficacy as monotherapies. Current efforts for enhancement of the therapeutic potency of OVs involve their combination with other therapy modalities, aiming at the concomitant exploitation of complementary tumor weaknesses. In this context, microtubule-targeting agents (MTAs) pose as an enticing option, as they perturb microtubule dynamics and function, induce cell-cycle arrest, and cause mitotic cell death. MTAs induce therapeutic benefit through cancer-cell-autonomous and non-cell-autonomous mechanisms and are a main component of the standard of care for different malignancies. However, off-target effects and acquired resistance involving distinct cellular and molecular mechanisms may limit the overall efficacy of MTA-based therapy. When combined, OVs and MTAs may enhance therapeutic efficacy through increases in OV infection and immunogenic cell death and a decreased probability of acquired resistance. In this review, we introduce OVs and MTAs, describe molecular features of their activity in cancer cells, and discuss studies and clinical trials in which the combination has been tested.

Acute myeloid leukemia (AML) is a notably lethal disease, characterized by malignant clonal proliferation of hematopoietic stem cells in the bone marrow. This study seeks to unveil potential therapeutic targets for AML, using a combined approach of microarray analysis and Mendelian randomization (MR). We collected data samples from the Gene Expression Omnibus (GEO) database and extracted pQTL data from genome-wide association studies (GWAS) to identify overlapping genes between the DEGs and GWAS data. Gene enrichment and pathway annotation analyses were performed on these genes. Furthermore, we validated gene expression levels and assessed their clinical relevance. By taking the intersection of these gene sets, we obtained a list of co-expressed genes, including four upregulated genes (REC8, TPM2, ZMIZ1, CD82) and two downregulated genes (IFNAR1, TMCO3). MR analysis demonstrated that genetically predicted protein levels of CD82, REC8, ZMIZ1, and TPM2 were significantly associated with increased odds of AML, while IFNAR1 and TMCO3 showed a protective effect. Gene ontology and KEGG pathway analyses revealed significant enrichment in functions related to female gamete generation, meiosis, p53 signaling pathway, and cardiac muscle contraction. Differences in immune cell profiles were observed between AML survivors and those with poor prognosis, including lower levels of neutrophils and higher levels of follicular helper T cells in the latter group. This study identifies a causal relationship between gene expression and AML and highlights the potential role of REC8 in leukemogenesis, possibly through its impact on gametocyte meiotic abnormalities. The findings provide new insights into the prevention and treatment of leukemia.

Dysregulation of the epigenomic landscape of tumor cells has been implicated in the pathogenesis of pancreatic cancer. However, these alterations are not only restricted to neoplastic cells. The behavior of other cell populations in the tumor stroma such as cancer-associated fibroblasts, immune cells, and others are mostly regulated by epigenetic pathways. Here, we present an overview of the main cellular and acellular components of the pancreatic cancer tumor microenvironment and discuss how the epigenetic mechanisms operate at different levels in the stroma to establish a differential gene expression to regulate distinct cellular phenotypes contributing to pancreatic tumorigenesis.

Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.

Cancer remains a significant risk to human health. Nanomedicine is a new multidisciplinary field that is garnering a lot of interest and investigation. Nanomedicine shows great potential for cancer diagnosis and treatment. Specifically engineered nanoparticles can be employed as contrast agents in cancer diagnostics to enable high sensitivity and high-resolution tumor detection by imaging examinations. Novel approaches for tumor labeling and detection are also made possible by the use of nanoprobes and nanobiosensors. The achievement of targeted medication delivery in cancer therapy can be accomplished through the rational design and manufacture of nanodrug carriers. Nanoparticles have the capability to effectively transport medications or gene fragments to tumor tissues via passive or active targeting processes, thus enhancing treatment outcomes while minimizing harm to healthy tissues. Simultaneously, nanoparticles can be employed in the context of radiation sensitization and photothermal therapy to enhance the therapeutic efficacy of malignant tumors. This review presents a literature overview and summary of how nanotechnology is used in the diagnosis and treatment of malignant tumors. According to oncological diseases originating from different systems of the body and combining the pathophysiological features of cancers at different sites, we review the most recent developments in nanotechnology applications. Finally, we briefly discuss the prospects and challenges of nanotechnology in cancer.

TANK-binding kinase 1 (TBK1) is a member of the IKK family and plays a crucial role in the activation of non-canonical NF-κB signaling and type I interferon responses. The aberrant activation of TBK1 contributes to the proliferation and survival of various types of tumor cells, particularly in specific mutational or tumorous contexts. Inhibitors targeting TBK1 are under development and application in both in vivo and in vitro settings, yet their clinical efficacy remains limited. Numerous literatures have shown that TBK1 can exhibit both tumor promoting and tumor inhibiting effects. TBK1 acts as a pivotal node within the innate immune pathway, mediating anti-tumor immunity through the activation of innate immune responses. Facilitating interferon-I (IFN-I) production represents a critical mechanism through which TBK1 bridges these processes. IFN has been shown to exert both beneficial and detrimental effects on tumor progression. Hence, the paradoxical role of TBK1 in tumor development may necessitate acknowledgment in light of its downstream IFN-I signaling cascade. In this paper, we review the signaling pathways mediated by TBK1 in various tumor contexts and summarize the dual roles of TBK1 and the TBK1-IFN pathways in both promoting and inhibiting tumor progression. Additionally, we highlight the significance of the TBK1-IFN pathway in clinical therapy, particularly in the context of immune response. We anticipate further advancements in the development of TBK1 inhibitors as part of novel cancer treatment strategies.

Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

Hepatocellular carcinoma (HCC) is a systemic disease with augmented malignant degree, high mortality and poor prognosis. Since the establishment of the immune mechanism of tumor therapy, people have realized that immunotherapy is an effective means for improvement of HCC patient prognosis. Oncolytic virus is a novel immunotherapy drug, which kills tumor cells and exempts normal cells by directly lysing tumor and inducing anti-tumor immune response, and it has been extensively examined as an HCC therapy. This editorial discusses oncolytic viruses for the treatment of HCC, emphasizing viral immunotherapy strategies and clinical applications related to HCC.

Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.

As key modulators of the immune response, interferons play critical roles following infection and during the pathogenesis of cancer. The idea that these cytokines might be developed as new therapies emerged soon after their discovery. While enthusiasm for this approach to cancer therapy has waxed and waned over the ensuing decades, recent advances in cancer immunotherapy and our improved understanding of the tumor immune environment have led to a resurgence of interest in this unique class of biologic drug. Here, we review how interferons influence the growth of colorectal cancers (CRCs) and highlight new insights into how interferons and drugs that modulate interferon expression might be most effectively deployed in the clinic.

This review addresses interferon (IFN) signaling in immune cells and the tumor microenvironment (TME) and examines how this affects cancer progression. The data reveal that IFNs exert dual roles in cancers, dependent on the TME, exhibiting both anti-tumor activity and promoting cancer progression. We discuss the abnormal IFN signaling induced by cancerous cells that alters immune responses to permit their survival and proliferation.

Tumor microenvironment (TME)-induced nanocatalytic therapy is a promising strategy for cancer treatment, but the low catalytic efficiency limits its therapeutic efficacy. Single-atom catalysts (SACs) are a new type of nanozyme with incredible catalytic efficiency. Here, a single-atom manganese (Mn)-N/C nanozyme is constructed. Mn-N/C catalyzes the conversion of cellular H2O2 to ∙OH through a Fenton-like reaction and enables the sufficient generation of reactive oxygen species (ROS), which induces immunogenic cell death (ICD) of tumor cells and significantly promotes CD8+T anti-tumor immunity. Moreover, RNA sequencing analysis reveals that Mn-N/C treatment activates type I interferon (IFN) signaling, which is critical for Mn-N/C-mediated anti-tumor immune response. Mechanistically, the release of cytosolic DNA and Mn2+ triggered by Mn-N/C collectively activates the cGAS-STING pathway, subsequently stimulating type I IFN induction. A highly efficient single-atom nanozyme, Mn-N/C, which enhances anti-tumor immune response and exhibits synergistic therapeutic effects when combined with the anti-PD-L1 blockade, is proposed.

This study aimed to investigate whether interferon-alpha 1 (IFNA1) is predictive of Ankylosing spondylitis (AS) progression and treatment response to Tumour necrosis factor inhibitors (TNFis).

Data of 50 AS patients receiving TNFi for 24 weeks were retrospectively analysed. AS patients who reached the Assessment of Spondyloarthritis International Society 40 response at the W24 were classified as responders to TNFi treatment; otherwise, they were classified as nonresponders. Human fibroblast-like synoviocytes (HFLS) isolated from AS patients (AS-HFLS) were used for in vitro validation.

When the IFNA1 expression level was used to diagnose AS patients, an area under the curve of 0.895 was yielded (P < .001). Pearson correlation analysis showed negative correlations between IFNA1 expression, C-reactive protein (CRP) level, Bath AS Disease Activity Index scores, AS Disease Activity Score with CRP, and the production of inflammatory cytokines. An increased IFNA1 expression level was found to be associated with a better treatment response to TNFi. IFNA1 overexpression could protect HFLS against inflammatory response in the setting of AS.

Blood IFNA1 deficiency is correlated with inflammatory cytokine production and disease activity and is indicative of unsatisfied response to TNFi treatment in AS patients.

Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8+ T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8+ T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8+ T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.

Transcriptional profiling demonstrated markedly reduced type I IFN gene expression in untreated mycosis fungoides (MF) skin lesions compared with that in healthy skin. Type I IFN expression in MF correlated with antigen-presenting cell-associated IRF5 before psoralen plus UVA therapy and epithelial ULBP2 after therapy, suggesting an enhancement of epithelial type I IFN. Immunostains confirmed reduced baseline type I IFN production in MF and increased levels after psoralen plus UVA treatment in responding patients. Effective tumor clearance was associated with increased type I IFN expression, enhanced recruitment of CD8+ T cells into skin lesions, and expression of genes associated with antigen-specific T-cell activation. IFNk, a keratinocyte-derived inducer of type I IFNs, was increased by psoralen plus UVA therapy and expression correlated with upregulation of other type I IFNs. In vitro, deletion of keratinocyte IFNk decreased baseline and UVA-induced expression of type I IFN and IFN response genes. In summary, we find a baseline deficit in type I IFN production in MF that is restored by psoralen plus UVA therapy and correlates with enhanced antitumor responses. This may explain why MF generally develops in sun-protected skin and suggests that drugs that increase epithelial type I IFNs, including topical MEK and EGFR inhibitors, may be effective therapies for MF.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor, that is refractory to standard treatment and to immunotherapy with immune-checkpoint inhibitors (ICI). Noteworthy, melanoma brain metastases (MM-BM), that share the same niche as GBM, frequently respond to current ICI therapies. Epigenetic modifications regulate GBM cellular proliferation, invasion, and prognosis and may negatively regulate the cross-talk between malignant cells and immune cells in the tumor milieu, likely contributing to limit the efficacy of ICI therapy of GBM. Thus, manipulating the tumor epigenome can be considered a therapeutic opportunity in GBM.

Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were performed to study the differences in the constitutive expression profiles of GBM vs MM-BM cells, compared to the extracranial MM cells and to investigate the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine among the different tumor cells. The prognostic relevance of DHA-modulated genes was tested by Cox analysis in a TCGA GBM patients' cohort.

The most striking differences between GBM and MM-BM cells were found to be the enrichment of biological processes associated with tumor growth, invasion, and extravasation with the inhibition of MHC class II antigen processing/presentation in GBM cells. Treatment with guadecitabine reduced these biological differences, shaping GBM cells towards a more immunogenic phenotype. Indeed, in GBM cells, promoter hypomethylation by guadecitabine led to the up-regulation of genes mainly associated with activation, proliferation, and migration of T and B cells and with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% showed a significant prognostic relevance. Moreover, a large set of immune-related upstream-regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and MM cells: DHA-activated URs enriched for biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and in Type I/II/III IFN-mediated signaling; conversely, DHA-inhibited URs were involved in metabolic and proliferative pathways.

Epigenetic remodeling by guadecitabine represents a promising strategy to increase the efficacy of cancer immunotherapy of GBM, supporting the rationale to develop new epigenetic-based immunotherapeutic approaches for the treatment of this still highly deadly disease.

Type I interferon (IFN-I) plays a critical role in host cancer immunosurveillance, but its expression is often impaired in the tumor microenvironment. We aimed at testing the hypothesis that cationic lipid nanoparticle delivery of interferon β (IFNβ)-encoding plasmid to tumors is effective in restoring IFNβ expression to suppress tumor immune evasion. We determined that IFN-I function in tumor suppression depends on the host immune cells. IFN-I activates the expression of Cxcl9 and Cxcl10 to enhance T cell tumor infiltration. RNA-Seq detected a low level of IFNα13 and IFNβ in colon tumor tissue. scRNA-Seq revealed that IFNβ is expressed in immune cell subsets in non-neoplastic human tissues and to a lesser degree in human colon tumor tissues. Forced expression of IFNα13 and IFNβ in colon tumor cells up-regulates major histocompatibility complex I (MHC I) expression and suppresses colon tumor growth in vivo. In human cancer patients, IFNβ expression is positively correlated with human leukocyte antigen (HLA) expression, and IFN-I signaling activation correlates with the patient response to PD-1 blockade immunotherapy. To translate this finding to colon cancer immunotherapy, we formulated a 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-cholesterol-encapsulated IFNβ-encoding plasmid (IFNBCOL01). IFNBCOL01 transfects colon tumor cells to express IFNβ to increase the level of MHC I expression. IFNBCOL01 therapy transfects tumor cells and tumor-infiltrating immune cells to produce IFNβ to activate MHC I and granzyme B expression and inhibits colon tumor growth in mice. Our data determine that lipid nanoparticle delivery of IFNβ-encoding plasmid DNA enhances tumor immunogenicity and T cell effector function to suppress colon tumor growth in vivo.

There is an association between cancer and increased ribosome biogenesis. At present, the RPL7L1 (60S Ribosomal Protein L7-Like 1) were less reported by literature search. Study reports that RPL7L1 is associated with mouse embryonic and skeletal muscle. The study of RPL7L1 on tumors has not been reported.

Our team downloaded the pan-cancer dataset that is uniformly normalized from the UCSC database (N=19131). Our study examined the relationship between RPL7L1 expression level and clinical prognosis with methylation, anti-tumour immunity, functional states, MSI, TMB, DNSss, LOH and chemotherapeutic responses in 43 cancer types and subtypes.

RPL7L1 was overexpressed in nine tumor types. Gene mutation, tumor microenvironment and methylation modification of RPL7L1 plays a key role in patient prognosis. And the high expression of RPL7L1 was associated with TMB, MSI, LOH especially LIHC and HNSC. We experimentally verified that genes can promote the proliferation and migration of tumor cells. Our study suggested that RPL7L1 biomarker can be used for treating cancer, detecting it, and predicting its prognosis.

Oral administration is the most preferred approach for treating colon diseases, and in situ vaccination has emerged as a promising cancer therapeutic strategy. However, the lack of effective drug delivery platforms hampered the application of in situ vaccination strategy in oral treatment of colorectal cancer (CRC). Here, we construct an oral core-shell nanomedicine by preparing a silk fibroin-based dual sonosensitizer (chlorin e6, Ce6)- and immunoadjuvant (imiquimod, R837)-loaded nanoparticle as the core, with its surface coated with plant-extracted lipids and pluronic F127 (p127). The resultant nanomedicines (Ce6/R837@Lp127NPs) maintain stability during their passage through the gastrointestinal tract and exert improved locomotor activities under ultrasound irradiation, achieving efficient colonic mucus infiltration and specific tumor penetration. Thereafter, Ce6/R837@Lp127NPs induce immunogenic death of colorectal tumor cells by sonodynamic treatment, and the generated neoantigens in the presence of R837 serve as a potent in situ vaccine. By integrating with immune checkpoint blockades, the combined treatment modality inhibits orthotopic tumors, eradicates distant tumors, and modulates intestinal microbiota. As the first oral in situ vaccination, this work spotlights a robust oral nanoplatform for producing a personalized vaccine against CRC.

Chemokines are small molecules that function as chemotactic factors which regulate the migration, infiltration, and accumulation of immune cells. Here, we comprehensively assess the structural and functional role of chemokines, examine the effects of chemokines that are present in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME), specifically those produced by cancer cells and stromal components, and evaluate their impact on immune cell trafficking, both in promoting and suppressing anti-tumor responses. We further explore the impact of chemokines on patient outcomes in PDAC and their role in the context of immunotherapy treatments, and review clinical trials that have targeted chemokine receptors and ligands in the treatment of PDAC. Lastly, we highlight potential strategies that can be utilized to harness chemokines in order to increase cytotoxic immune cell infiltration and the anti-tumor effects of immunotherapy.

This study aims to elucidate the involvement of triple-negative breast cancer (TNBC)-derived extracellular vesicles in metastasis. The loss of components in the type 1 interferon (IFN1) signaling pathway has been linked to the promotion of metastasis. However, IFN1 signaling induces immunological dormancy and promotes tumorigenesis. Our hypothesis was that TNBC cells release tumor-derived extracellular vesicles (TEVs) that promote metastasis in an IFN1-independent manner.

Two murine TNBC models and transgenic mice were used to examine the role of IFN1 in TNBC progression to metastasis. Reserpine was employed to determine the effect of TEV education on TNBC progression and overall survival. EVs from cancer cells treated with vehicle and reserpine and from the serum of tumor-bearing mice receiving reserpine were examined to determine changes in EV release and EV content.

TNBC cells progress to metastasis in mice lacking the IFN1-induced gene cholesterol-25 hydroxylase (CH25H) or expressing the IFNAR1S526 knock-in that cannot be downregulated. Reserpine suppresses EV release from TNBC cells in vitro and in vivo. Western blot analysis demonstrated reserpine decreased NUPR1 protein levels in EVs. RNAseq analysis demonstrated that endothelial cells lacking CH25H treated with TEVs exhibited increased NUPR1 expression that was decreased by adding reserpine with the TEVs. NUPR1 overexpression upregulated genes that mediate TEV biogenesis and incorporation. Knockdown of NUPR1 with shRNA decreased the release of TEVs.

In conclusion, our study suggests that TNBC is driven by aberrant packaging of NUPR1 into TEVs which were transferred into recipient cells to activate pro-metastatic transcription driven by NUPR1.

Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.