Immunogenicity of cell death and cancer immunotherapy with immune checkpoint inhibitors

Cellular and Molecular Immunology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 10, 2024

While immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the clinical management of various malignancies, a large fraction patients are refractory to ICIs employed as standalone therapeutics, necessitating development combinatorial treatment strategies. Immunogenic cell death (ICD) inducers have attracted considerable interest partners for ICIs, at least in part owing their ability initiate tumor-targeting adaptive response. However, compared either approach alone, regimens involving ICD and not always shown superior activity. Here, we discuss accumulating evidence on therapeutic interactions between oncological settings, identify key factors that may explain discrepancies preclinical findings, propose strategies address existing challenges increase efficacy these combinations cancer.

Язык: Английский

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Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial–Mesenchymal Transition

Cancers, Год журнала: 2025, Номер 17(2), С. 228 - 228

Опубликована: Янв. 12, 2025

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes to treat due its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk metastasis, lower overall survival compared other subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds taxanes) continues be standard treatment for TNBC, often limited long-term efficacy. tumors are heterogeneous, displaying diverse mutation profile considerable chromosomal instability, which complicates therapeutic interventions. The development chemoresistance frequently associated process epithelial–mesenchymal transition (EMT), during epithelial tumor cells acquire mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing effectiveness chemotherapeutics. It has also been suggested that EMT plays central role stem cells. Hence, there growing interest exploring small-molecule inhibitors target as future strategy overcoming resistance improving outcomes patients TNBC. review focuses on progression drug emphasis these processes. We present TNBC-specific EMT-related features, key protein markers, various signaling pathways involved. discuss important mechanisms factors related within context EMT, highlighting improve patients’ outcomes.

Язык: Английский

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Reinforcing cancer immunotherapy with engineered porous hollow mycobacterium tuberculosis loaded with tumor neoantigens

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(2), С. e010150 - e010150

Опубликована: Фев. 1, 2025

Background Enhancing antigen cross-presentation is essential for the development of a tumor neoantigen vaccine. One approach to stimulate antigen-presenting cells (APCs) uptake neoantigens. Mycobacterium tuberculosis (MTb) contains pathogen-associated molecular patterns (PAMPs) recognized by APCs and adhesion molecules that facilitate MTb invasion APCs. Therefore, we suggest using as carrier enhance APC phagocytosis neoantigens, thereby promoting cross-presentation. Methods The successful preparation (phMTb) was confirmed through electron confocal microscopy. Fluorescence microscopy used detect PAMPs on phMTb well observe its role in aiding dendritic (DCs) into endosomes or lysosomes. Flow cytometry assess retention phMTb, investigate DCs, evaluate their activation maturation status, examine presentation analyze immune draining lymph nodes tissues. efficacy vaccine formulations combination with anti-programmed cell death protein 1 (PD-1) antibody therapy assessed MC38 mouse models. Adverse effects were evaluated H&E staining major organs, assessment reproductive capability detection biochemical indices. Results engineered porous hollow successfully encapsulated model without adjuvant CpG. retained surface, similar parental MTb, enhancing DC containing neoantigens Vaccines formulated facilitated maturation, activation, promoted migration phMTb-laden DCs nodes, effector memory CD8 + T lymphocyte function. In murine models, immunization phMTb-formulated vaccines elicited robust tumor-specific cytotoxic response minimal adverse effects. Additionally, vaccination effectively reversed tumor’s immune-suppressive microenvironment. Concurrent administration PD-1 exhibited significant synergistic therapeutic Conclusions results our study highlight potential clinical translation personalized carrier.

Язык: Английский

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Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy

Cancer Cell, Год журнала: 2025, Номер 43(3), С. 503 - 518.e10

Опубликована: Март 1, 2025

Highlights•STING-induced PD-L1hi Tu.Mons dominate the resistance to STING agonist therapy•Cell-intrinsic PD-L1 induced by STING-IFN-I axis drives protumoral Tu.Mons•TLR2 activation rewires signaling reduce cell-intrinsic PD-L1•STING combined with TLR2 pre-activation shows enhanced antitumor efficacySummarySTING is an important DNA sensing machinery in initiating immune response, yet therapies targeting have shown poor outcomes clinical trials. Here, we reveal that induces tumor monocytes (Tu.Mons) against therapy. Cell-intrinsic PD-L1, STING-IRF3-IFN-I axis, identified as driving factor for Tu.Mons. Notably, TLR2-activated resist STING-induced upregulation of and associated functions. Mechanistically, stimulation remodels facilitating TRAF6 interaction, which suppresses IRF3-IFN-I response enhances NF-κB activation. Moreover, demonstrate combining agonists pretreatment significantly improves efficacy murine syngeneic humanized models. Our findings uncover a aspect mediated propose promising strategy boost immunity fine-tuning outputs.Graphical abstract

Язык: Английский

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Inhibition of SIRT4 promotes bladder cancer progression and immune escape via attenuating CD8+ T cells function

International Immunopharmacology, Год журнала: 2025, Номер 147, С. 113906 - 113906

Опубликована: Янв. 5, 2025

Язык: Английский

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Monitoring cellular dynamics upon infection using a holotomography-based approach

Methods in cell biology, Год журнала: 2025, Номер unknown, С. 109 - 118

Опубликована: Янв. 1, 2025

Язык: Английский

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Inhibition of EMT driver PTK6 enhances anti-tumor immune responses against triple-negative breast cancer

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

ABSTRACT The non-receptor tyrosine kinase PTK6 is expressed in 70% of triple negative breast cancers (TNBC) and an oncogenic driver epithelial-mesenchymal transition (EMT). EMT promotes metastasis immune evasion TNBC. Therefore, targeting drivers could reverse these properties lead to more favorable outcomes. Treatment TNBC tumors with a small molecule inhibitor (P21d) suppressed their growth vivo . Tumor inhibition by P21d dependent on induced response because: 1) observed immunocompetent, but not immunodeficient, mice; 2) increases tumor-infiltrating CD8 + T NK cells decreases immunosuppressive myeloid-derived suppressor cells; 3) tumor abrogated co-treatment or cell-depleting antibodies. These effects cytotoxic TILs are phenocopied the knockdown tumoral SNAIL, which supports as mechanism for enhanced anti-tumor response. RNA sequencing (RNA-seq) profiling P21d-treated also revealed changes consistent activation identified CXCL10 critical chemokine intratumorally that recruitment NK/CD8+ site, leading inhibition. Our study highlights novel microenvironmental functions important consequences new immunotherapeutic approaches

Язык: Английский

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Evolutionary trajectories of immune escape across cancers

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 18, 2025

Abstract Immune escape is a critical hallmark of cancer progression and underlies resistance to multiple immunotherapies. However, it remains unclear when the genetic events associated with immune occur during development. Here, we integrate functional genomics studies immunomodulatory genes tumor evolution reconstruction approach infer across 38 types from Pan-Cancer Analysis Whole Genomes dataset. Different cancers favor mutations in different pathways. For example, antigen presentation machinery highly mutated colorectal adenocarcinoma, lung squamous cell carcinoma, chromophobe renal protein methylation pathway bladder transitional carcinoma adenocarcinoma. We also observe timing patterns instance, impacting involved cellular amino acid metabolism were more likely happen late pancreatic Mutations glucocorticoid receptor regulatory network tended early, while TNF pathways B-cell non-Hodgkin lymphoma. NOD1/2 signaling DNA binding transcription factor activity breast adenocarcinoma ovarian Together, these results delineate evolutionary trajectories highlight opportunities for improved immunotherapy cancer. Significance Despite its role progression, poorly understood. types. Our have important implications developing biomarkers immunoprevention treatment strategies

Язык: Английский

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Paradoxical control of multifocal mammary oncogenesis by radiation therapy

OncoImmunology, Год журнала: 2025, Номер 14(1)

Опубликована: Янв. 28, 2025

In an immunocompetent mouse model of multifocal, metachronous HR+ mammary carcinogenesis, we have recently demonstrated that a superior control primary neoplastic lesions by focal radiotherapy does not necessarily translate into improved oncosuppression at non-irradiated (pre)malignant tissues. These data point to link between local tumor and systemic oncogenesis remains be fully understood.

Язык: Английский

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NF-κB signaling and the tumor microenvironment in osteosarcoma: implications for immune evasion and therapeutic resistance

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Янв. 30, 2025

Osteosarcoma, a highly aggressive malignancy with generally poor prognosis, is characterized by tumor cells’ ability to evade immune responses and resist treatment. The nuclear transcription factor NF-κB signaling pathway crucial in regulating inflammatory reactions. It occupies central position the development of osteosarcoma microenvironment. This research aimed explore how influences recruitment polarization tumor-associated macrophages myeloid-derived suppressor cells, both which contribute immunosuppression. Furthermore, facilitates surveillance evasion cells altering expression checkpoint molecules, such as PD-L1. also enhances cell resistance chemotherapy radiotherapy activating anti-apoptotic pathways exacerbating treatment-induced inflammation. Potential therapeutic approaches include using inhibitors, possibly combination overcome mechanisms reshape antitumor responses. A thorough examination NF-κB’s role expected yield novel clinical treatment strategies, significantly improve patient prognosis targeting this key pathway.

Язык: Английский

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