Current and future immunotherapeutic approaches in pancreatic cancer treatment

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Июнь 4, 2024

Abstract Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type tumor have remained grim long time. Currently, it extremely challenging to prevent or detect early enough effective treatment because patients rarely exhibit symptoms there are no reliable indicators detection. Most advanced spreading that difficult treat, treatments like chemotherapy radiotherapy can only slightly prolong their life by few months. Immunotherapy has revolutionized pancreatic cancer, yet its effectiveness limited tumor's immunosuppressive hard-to-reach microenvironment. First, article explains microenvironment highlights wide range immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered chimeric antigen [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced cells, immune checkpoint inhibitors, immunomodulators, vaccines, strategies targeting myeloid in context contemporary knowledge future trends. Lastly, discusses main challenges ahead immunotherapy.

Язык: Английский

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Self-Cascaded Pyroptosis-STING Initiators for Catalytic Metalloimmunotherapy

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

Gasdermin (GSDM)-mediated pyroptosis involves the induction of mitochondrial damage and subsequent release DNA (mtDNA), which is anticipated to activate cGAS-STING pathway, thereby augmenting antitumor immune response. However, challenges lie in effectively triggering cancer cells subsequently enhancing activation with specificity. Herein, we developed intelligent self-cascaded pyroptosis-STING initiators cobalt fluoride (CoF2) nanocatalysts for catalytic metalloimmunotherapy. CoF2 a semiconductor structure enzyme-like activity generated substantial amount reactive oxygen species (ROS) under stimulation by endogenous H2O2 exogenous ultrasound. Importantly, discovered that Co-based nanomaterials themselves induce cells. Therefore, initially acted as inducers, caspase-1/GSDMD-dependent via Co2+ ROS, leading mtDNA release. Subsequently, were further utilized STING agonists specifically capable detecting pathway. These cascade events triggered robust response, modulating immunosuppressive tumor microenvironment into an immune-supportive state, providing favorable support therapy. This innovative strategy not only significantly impeded growth primary but also elicited response augment efficacy checkpoint inhibitors preventing distant progression. Overall, this study proposed self-cascade activating amplifying pathway specificity mediated pyroptosis, representing valuable avenue future

Язык: Английский

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Biometallic ions and derivatives: a new direction for cancer immunotherapy

Molecular Cancer, Год журнала: 2025, Номер 24(1)

Опубликована: Янв. 15, 2025

Biometallic ions play a crucial role in regulating the immune system. In recent years, cancer immunotherapy has become breakthrough treatment, achieving good efficacy wide range of cancers with its specificity and durability advantages. However, existing therapies still face challenges, such as tolerance escape. (e.g. zinc, copper, magnesium, manganese, etc.) can assist enhancing through activation cells, enhancement tumor antigen presentation, improvement microenvironment. addition, biometallic derivatives directly inhibit cell progression offer possibility effectively overcoming limitations current by promoting responses reducing immunosuppressive signals. This review explores potential application prospects immunotherapy, providing new ideas for future clinical metal part helping to guide development more effective safe therapeutic regimens.

Язык: Английский

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Agonists and Inhibitors of the cGAS-STING Pathway

Molecules, Год журнала: 2024, Номер 29(13), С. 3121 - 3121

Опубликована: Июнь 30, 2024

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is pivotal in immunotherapy. Several agonists and inhibitors the cGAS-STING have been developed evaluated for treatment various diseases. aim to activate STING, with dinucleotides (CDNs) being most common, while block enzymatic activity or DNA binding ability cGAS. Meanwhile, non-CDN compounds cGAS are also gaining attention. omnipresence vivo indicates that its overactivation could lead undesired inflammatory responses autoimmune diseases, which underscores necessity developing both pathway. This review describes molecular traits roles summarizes development inhibitors. information supposed be conducive design novel drugs targeting

Язык: Английский

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A next-generation STING agonist MSA-2: From mechanism to application

Journal of Controlled Release, Год журнала: 2024, Номер 371, С. 273 - 287

Опубликована: Июнь 1, 2024

Язык: Английский

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Biodegradable Long-Circulating Nanoagonists Optimize Tumor-Tropism Chemo-Metalloimmunotherapy for Boosted Antitumor Immunity by Cascade cGAS-STING Pathway Activation

ACS Nano, Год журнала: 2024, Номер 18(34), С. 23711 - 23726

Опубликована: Авг. 16, 2024

The activation of cyclic GMP-AMP synthase (cGAS) and stimulator interferon genes (STING) has been recognized as one the most promising immunotherapeutic strategies to induce innate antitumor immune responses. However, it is far from effective just activate cGAS-STING pathway, owing abundant immunosuppressive cells that infiltrate tumor microenvironment (TME) impair immunity. Here, we present smart design biodegradable Mn-doped mesoporous silica (MM) nanoparticles with metal–organic framework (MOF) gating hyaluronic acid (HA)-modified erythrocyte membrane (eM) camouflaging coload cisplatin (CDDP) SR-717 (a STING agonist) for long-circulating tumor-tropism synergistic chemo-metalloimmunotherapy by cascade activation. Once internalized cells, acidity/redox-responsive gated MOF rapidly disintegrates release exposes dual-responsive MM decompose CDDP release, thus inducing damage double-stranded DNA (dsDNA) in cancer cells. As tumor-specific antigens, these dsDNA fragments released can trigger enhance dendritic cell (DC) maturation cytotoxic T (CTL) infiltration, giving rise excellent therapeutic effects efficient regression. Overall, this custom-designed nanoagonist represents a paradigm nanotechnology realizing cooperation chemotherapy metalloimmunotherapy based on future oncological applications.

Язык: Английский

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Enhanced Antitumor Efficacy of STING Agonist MSA-2 by Lipid Nanoparticles Delivering Circular IL-23 mRNA and Platinum-Modified MSA-2 Combination

Materials Today Bio, Год журнала: 2025, Номер 30, С. 101446 - 101446

Опубликована: Янв. 5, 2025

A next-generation STING agonist MSA-2 is a promising tumor immunotherapy strategy. However, the methods for improving anti-tumor efficacy of are lot effort. We have demonstrated antitumor effect platinum-modified (MSA-2-Pt) was better than MSA-2. Here, we combined lipid nanoparticles delivering circular IL-23 mRNA (LNP@cIL-23) and MSA-2-Pt strategy, which showed good efficacy. Firstly, synthesized new series ionizable phospholipids formulated optimized an LNP36 mRNA. Then, combination LNP36@cIL-23 induced cell death immune activation in with single i.t. injection. Finally, significantly decreased melanoma B16F10 prolonged survival, demonstrating significant effects. This finding provides avenues strategies immunotherapy.

Язык: Английский

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Activating the cGAS-STING Pathway by Manganese-Based Nanoparticles Combined with Platinum-Based Nanoparticles for Enhanced Ovarian Cancer Immunotherapy

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Recent research has demonstrated that activating the cGAS-STING pathway can enhance interferon production and activation of T cells. A manganese complex, called TPA-Mn, was developed in this context. The reactive oxygen species (ROS)-sensitive nanoparticles (NPMn) loaded with TPA-Mn are developed. NPMn activates via cGAS (i.e., 1.6-fold enhancement P-STING), which turn increases secretion pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-2). This promotes dendritic cell maturation, enhances infiltration cytotoxic lymphocytes, reduces percentage immunosuppressive regulatory In addition, it is crucial to emphasize cisplatin-induced DNA damage potentially trigger pathway. NPMn, combination low-dose NPPt, a carrier Cis(IV) prodrug capable causing damage, augments significantly tumor immune microenvironment (TIME). Furthermore, combined anti-PD-1 antibody, NPPt+NPMn shows synergistic efficacy both ovarian cancer peritoneal metastases recurrence models. It not only effectively eliminates tumors but also induces strong memory response, providing promising strategy for clinical management cancer. work offers design manganese-based immunotherapy.

Язык: Английский

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Photoactivation of cGAS-STING Pathway and Pyroptosis by Endoplasmic Reticulum-Targeting Ruthenium(II) Complex for Cancer Immunotherapy

Inorganic Chemistry Frontiers, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

A cholic acid-modified ruthenium( ii ) (Ru1) photosensitizer was synthesized. Ru1 induced pyroptosis and sequentially engaged the downstream proteins p-TBK1 p-IRF3 within STING pathway, thus promoting elicitation of tumor immune responses.

Язык: Английский

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Dual inhibitors of DNMT and HDAC remodels the immune microenvironment of colorectal cancer and enhances the efficacy of anti-PD-L1 therapy

Pharmacological Research, Год журнала: 2024, Номер 206, С. 107271 - 107271

Опубликована: Июнь 19, 2024

Colorectal cancer is the second most prevalent and deadly worldwide. The emergence of immune checkpoint therapy has provided a revolutionary strategy for treatment solid tumors. However, less than 5 % colorectal patients respond to therapy. Thus, it great scientific significance develop "potentiators" In this study, we found that knocking down different DNMT HDAC isoforms could increase expression IFNs in cells, which can enhance effectiveness Therefore, combined inhibition cloud synergistically effect immunotherapy. We dual inhibitors C02S inhibit tumor growth immunocompetent mice but not immunocompromised nude mice, indicates exerts its antitumor effects through system. Mechanistically, ERVs, generated intracellular levels dsRNA then promotes RIG-I/MDA5-MAVS signaling pathway. Moreover, increased infiltration DCs T cells microenvironment, enhanced efficacy anti-PD-L1 MC38 CT26 model. These results confirmed activate pathway, remodel microenvironment therapy, provides new evidence solutions development "potentiator"

Язык: Английский

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