Enhance Cancer Immunotherapy Research Articles

Preclinical Evaluation of the Efficacy of Human Sirpα Antibodies for B-Cell Lymphoma Immunotherapy in Humanized Mouse Models

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets to enhance cancer immunotherapy against B-cell lymphomas. However, faithful and predictive preclinical tumor models of human B-cell lymphomas for the evaluation of therapeutics targeting human TAMs have not been established yet. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on Rag2-/-Il2rg-/- immunodeficient mice that express multiple human cytokines, such as M-CSF, IL-3, GM-CSF, and THPO (MITRG mice), and have been reconstituted with a human immune system (HIS) by transplantation of human CD34+ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both the human cell line (Raji)-derived and diffuse large B cell lymphoma (DLBCL) patient-derived xenograft tumors as well as the infiltration of human macrophages into these tumors. We examined the potential antitumor effect of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor-mediated phagocytosis of tumor cells by human macrophages. Combined treatment with rituximab and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy in a therapeutic model started after the engraftment of the tumor. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs towards a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of DLBCL patient-derived xenograft tumors in HIS-MITRG mice. Our findings thus support the utility of HIS-MITRG mice as a model for the preclinical in vivo evaluation of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs.

Targeting the PD-L1 cytoplasmic domain and its regulatory pathways to enhance cancer immunotherapy.

As a significant member of the immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) plays a critical role in cancer immune escape and has become an important target for cancer immunotherapy. Clinically approved drugs mainly target the extracellular domain of PD-L1. Recently, the small cytoplasmic domain of PD-L1 has been reported to regulate PD-L1 stability and function through multiple pathways. Therefore, the intracellular domain of PD-L1 and its regulatory pathways could be promising targets for cancer therapy, expanding available strategies for combined immunotherapy. Here, we summarize the emerging roles of the PD-L1 cytoplasmic domain and its regulatory pathways. The conserved motifs, homodimerization, and posttranslational modifications of the PD-L1 cytoplasmic domain have been reported to regulate the membrane anchoring, degradation, nuclear translocation, and glycosylation of PD-L1. This summary provides a comprehensive understanding of the functions of the PD-L1 cytoplasmic domain and evaluates the broad prospects for targeted therapy.

Enhanced cancer immunotherapy through synergistic ferroptosis and immune checkpoint blockade using cell membrane-coated nanoparticles

BackgroundImmune checkpoint blockade (ICB) has achieved unprecedented success in inhibiting the progression and metastasis of many cancers. However, ICB regents as a single treatment have a relatively low overall response rate due to the tumor’s low immunogenicity and immunosuppressive microenvironment. Herein, we report a PD-1 cellular membrane-coated ferroptosis nanoinducer to potentiate cancer immunotherapy toward triple-negative breast cancer.ResultsThis study demonstrates that PD-1 membrane-coated RSL3 nanoparticles (PD-1@RSL3 NPs) have the ability to disrupt the PD-1/PD-L1 axis, leading to the activation of antitumor immunity in breast cancer. In addition, the nanoparticles promote the induction of tumor cell ferroptosis through GPX4 inhibition, enhanced infiltration of CD8+ T cells, and maturation of dendritic cells. The potentiated antitumor immune response induced by PD-1@RSL3 NPs significantly delayed tumor progression and extended the survival rate of mice with breast cancer xenografts.ConclusionsOur study suggest the potential of PD-1@RSL3 NPs as an effective therapeutic approach for breast cancer by promoting tumor cell ferroptosis and inducing antitumor immunity.

An Overview of the Immune Modulatory Properties of Long Non-Coding RNAs and Their Potential Use as Therapeutic Targets in Cancer.

Long non-coding RNAs (lncRNAs) play pivotal roles in regulating immune responses, immune cell differentiation, activation, and inflammatory processes. In cancer, they are gaining prominence as potential therapeutic targets due to their ability to regulate immune checkpoint molecules and immune-related factors, suggesting avenues for bolstering anti-tumor immune responses. Here, we explore the mechanistic insights into lncRNA-mediated immune modulation, highlighting their impact on immunity. Additionally, we discuss their potential to enhance cancer immunotherapy, augmenting the effectiveness of immune checkpoint inhibitors and adoptive T cell therapies. LncRNAs as therapeutic targets hold the promise of revolutionizing cancer treatments, inspiring further research in this field with substantial clinical implications.

CYT-338 NK Cell Engager Mutispecific Antibody Engagement of NKp46 Activation Receptor Overcomes Anti-CD38 Mab Mediated Fratricide of NK Cells and Accords Enhanced Cancer Immunotherapy

Background and Significance: Despite the clinical success of the first anti-CD38 targeted monoclonal antibody, daratumumab, approved for the treatment of multiple myeloma (MM), significant challenges remain such as CD38 antigen loss/internalization and/or natural killer (NK) cell fratricide resulting in resistance to treatment over time. Study Design and Methods: To overcome the above-mentioned challenges, Cytovia has utilized its proprietary multifunctional tetravalent Flex Engager TM bispecific antibody IgG scaffold platform that contains a flexible linker for simultaneous engagement of effector immune cells and tumors targets. Through this, we generated CYT-338, an NK cell engager mutispecific antibody that targets CD38 on MM tumors and NKp46 and CD16 activation receptors on NK cells to mediate potent NK cell redirected killing of MM tumor cells more efficaciously than daratumumab. In serial killing assays against MM tumors, CYT-338 reversed dysfunctional NK cells to its original activation state and prevented exhaustion of killing activity of NK cells over time. In addition, we have also previously reported that CYT-338 has a higher potency over daratumumab for antibody dependent cellular phagocytosis (ADCP) of MM tumors. Preclinically,CYT-338 shows significantly reduced NK cell fratricide compared to daratumumab but the reason for this was unknown. We hypothesized that CYT-338 could overcome anti-CD38 mAb mediated fratricide of NK cells by engaging NKp46 activation receptor. To this end we incubated peripheral blood NK cells (PBNK) with either anti-CD38 mAb, daratumumab, CYT-338 or human IgG1 isotype control either in the presence or absence of blocking anti-NKp46 mAb (IgG1) for 24 hrs at 37 oC and stained with Annexin V apoptosis and Zombie NIR viability dye and analyzed NK fratricide by flow cytometry. We also evaluated the ability of anti-NKp46 mAb to inhibit daratumumab-mediated fratricide of NK cells under the same conditions. Current Status: Through functional preclinical investigations, we have been able to deconvolute the novel molecular mechanisms whereby NKp46 and CD16 co-engagement signals by CYT-338 on NK cells are able to overcome the CD38 apoptotic fratricide signals induced by the single anti-CD38 mAb. Specifically, we have found that blockade of CYT-338 binding to NKp46 by anti-NKp46 IgG1 antibody reversed the fratricide protection provided by CYT-338, indicating that the fratricide protection was mediated by NKp46 activation signals. In addition, the single anti-NKp46 mAb was able to inhibit daratumumab-mediated NK cell fratricide providing direct evidence that daratumumabmediated fratricide can also be reversed by engagement of NKp46 activation receptor. Conclusions: The unique NKp46 activation mechanism provided by CYT-338 for reducing NK cell fratricide and maintaining NK cell levels together with the enhanced potency including reversal of NK cell dysfunction makes it an attractive best-in-class anti-CD38 therapeutic against MM compared to daratumumab. These results support the development of CYT-338 in both monotherapy and combination with other complementary immunotherapy agents being developed or approved for MM. A first-in-human Phase 1 study targeting patients with relapsed/refractory MM is in development in the U.S.

Sialic Acid-Functionalized Pyroptosis Nanotuner for Epigenetic Regulation and Enhanced Cancer Immunotherapy.

The efficacy of immune checkpoint blockade (ICB) in promoting an immune response against tumors still encounters challenges such as low response rates and off-target effects. Pyroptosis, an immunogenic cell death (ICD) mechanism, holds the potential to overcome the limitations of ICB by activating and recruiting immune cells. However, the expression of the pyroptosis-related protein Gasdermin-E(GSDME) in some tumors is limited due to mRNA methylation. To overcome this obstacle, sialic acid-functionalized liposomes coloaded with decitabine, a demethylation drug, and triclabendazole, a pyroptosis-inducing drug are developed. This nanosystem primarily accumulates at tumor sites via sialic acid and the Siglec receptor, elevating liposome accumulation in tumors up to 3.84-fold at 24 h and leading to the upregulation of pyroptosis-related proteins and caspase-3/GSDME-dependent pyroptosis. Consequently, it facilitates the infiltration of CD8+ T cells into the tumor microenvironment and enhances the efficacy of ICB therapy. The tumor inhibition rate of the treatment group is 89.1% at 21 days. This study highlights the potential of sialic acid-functionalized pyroptosis nanotuners as a promising approach for improving the efficacy of ICB therapy in tumors with low GSDME expression through epigenetic alteration and ICD.

Stem cell-derived paracrine factors by modulated reactive oxygen species to enhance cancer immunotherapy

Herein, we present an approach for manipulating paracrine factors and signaling pathways in adipose-derived stem cells (ADSCs) to achieve highly effective tumor immunotherapy. Our method involves precise control of reactive oxygen species concentration using the CD90-maleimide-pluronic F68-chlorin e6 conjugate (CPFC) to create ACPFC, which is then attached to ADSCs through the CD90 receptor-specific interaction. By regulating the irradiated laser power, ACPFC promotes signaling pathways such as cascade-3, VEGFR2, α2β1, C3AR1, CR1–4, and C5AR1, leading to the secretion of various inflammatory cytokines such as IFN-γ, TGF-β, and IL-6, while inhibiting AKT, ERK, NFkB, PAR1, and PAR3/4 signaling pathways to reduce the secretion of cell growth factors like TIMP-1, TIMP-2, VEGF, Ang-2, FGF-2, and HGF. When ACPFC is injected intravenously into a tumor animal model, it autonomously targets and accumulates at the tumor site, and upon laser irradiation, it generates various anti-inflammatory factors while reducing angiogenesis growth factors. The resulting antitumor response recruits CD3+CD8+ cytotoxic T cells and CD3+CD4+ helper T cells into the tumor and spleen, leading to highly effective melanoma and pancreatic tumor treatment in mice. Our technology for regulating stem cell paracrine factors holds significant promise for the treatment of various diseases.

A drug-delivery depot for epigenetic modulation and enhanced cancer immunotherapy

DNA methyltransferase inhibitors (DNMTis) have found widespread application in the management of cancer. Zebularine (Zeb), functioning as a demethylating agent, has exhibited notable advantages and enhanced therapeutic efficacy in the realm of tumour immunotherapy. Nevertheless, due to its lack of targeted functionality, standalone Zeb therapy necessitates the administration of a substantially higher dosage. In this investigation, we have devised an innovative nanodrug formulation, comprising the DNA methyltransferase inhibitor Zeb and pH-responsive chitosan (CS), hereinafter referred to as CS-Zeb nanoparticles (NPs). Our findings have unveiled that CS-Zeb NPs manifest heightened drug release within an acidic milieu (pH 5.5) in comparison to a neutral environment (pH 7.4). Furthermore, in vivo studies have conclusively affirmed that, in contrast to equivalent quantities of Zeb in isolation, the nanocomplex significantly curtailed tumour burden and protracted the survival duration of the B16F10 tumour-bearing murine model. Additionally, CS-Zeb NPs elicited an augmentation of CD8+ T cells within the peripheral circulation of mice and tumour-infiltrating lymphocytes (TILs). Notably, the dosage of CS-Zeb NPs was reduced by a remarkable 70-fold when juxtaposed with Zeb administered in isolation. To summarise, our study underscores the potential of CS-Zeb NPs as an alternative chemotherapeutic agent for cancer treatment.

Platelet membrane fusion liposome loaded with type I AIE photosensitizer to induce chemoresistance cancer pyroptosis and immunogenic cell death for enhancing cancer immunotherapy

Cancer cells often develop resistance to chemotherapy induced apoptosis, and targeting non-apoptosis-related pathways is a potential anti-drug resistant tumor strategy. Here, we designed a platelet membrane fusion liposome nanovesicle system (named TFL) loaded with type I aggregation induced-emission (AIE) photosensitizer (TBP-2), which is used to promote the pyroptosis and immunogenic cell death (ICD) of chemoresistance breast cancer cells. Because of the highly expressed P-selectin protein in platelets, TFL can target the highly expressed CD44 receptor in chemoresistance breast cancer cells and deliver TBP-2 molecules to these cells. Under the irradiation of external light sources, TBP-2 achieves type-I photodynamic therapy (PDT), generating a large number of hydroxyl free radicals, inducing pyroptosis and ICD of chemoresistance cancer cells, promoting DC cell maturation and T cell infiltration. In vivo animal experiments have shown that the TFL system can promote T cell immunity, slow down distal chemoresistance tumor growth, achieve immune memory effect, and inhibit chemoresistance tumor rechallenge. Compared with high-dose chemotherapy, TFL + L has better immune stimulation and therapeutic effect on drug-resistant breast cancer. This system may become an adjuvant therapy for clinical chemotherapy in the future, further enhancing the immune response and therapy effect of drug-resistant tumors.

Near‐infrared laser‐activated aggregation‐induced emission nanoparticles boost tumor carbonyl stress and immunotherapy of breast cancer

AbstractThe induction of tumor carbonyl stress is reported to efficiently revert immune suppression in the tumor microenvironment and enhance cancer immunotherapy. However, low oxygen concentration due to inherent tumor hypoxia limits its catalytic effect. Herein, an injectable thermosensitive hydrogel system (named APH) is developed for co‐loading of near‐infrared (NIR) aggregation‐induced emission (AIE) nanoparticles and plasma amine oxidase (PAO) for boosting carbonyl stress and enhancing antitumor immunity. Upon 808 nm NIR laser irradiation, the AIE nanoparticles trigger a mild‐temperature (around 45°C) photothermal effect in the tumor site, which significantly relieves tumor hypoxia and promotes the catalytic effect of released PAO to inhibit the growth of Myeloid‐derived suppressor cells. Remarkably, the synergistic therapeutic effect of APH is verified through a significant inhibitory effect on the distant tumor, enhanced immune memory, and effective suppression of postoperative recurrence, rechallenge, and metastasis. Overall, the combined effect of AIE‐mediated photothermal therapy and carbonyl stress by APH upon NIR irradiation therapy can significantly activate cancer immunotherapy, making it a promising treatment approach for cancer treatment.

Redirecting Antigens by Engineered Photosynthetic Bacteria and Derived Outer Membrane Vesicles for Enhanced Cancer Immunotherapy.

Significant strides have been made in the development of cancer vaccines to combat malignant tumors. However, the natural immunosuppressive environment within tumors, known as the tumor microenvironment (TME), hampers the uptake and presentation of antigens by antigen-presenting cells (APCs) within the tumor itself. This limitation results in inadequate activation of immune responses against cancer. In contrast, immune cells in peritumoral tissue maintain their normal functions. In this context, we present an interesting approach to enhance cancer immunotherapy by utilizing engineered photosynthetic bacteria (PSB) and their outer membrane vesicles (OMVPSB) to capture and transport antigens to the outer regions of the tumor. We modified PSB with maleimide (PSB-MAL), which, when exposed to near-infrared (NIR) laser-mediated photothermal therapy (PTT), induced extensive cancer cell death and the release of tumor antigens. Subsequently, the NIR-phototactic PSB-MAL transported these tumor antigens to the peripheral regions of the tumor under NIR laser exposure. Even more intriguingly, PSB-MAL-derived OMVPSB-MAL effectively captured and delivered antigens to tumor-draining lymph nodes (TDLNs). This facilitated enhanced antigen presentation by mature and fully functional APCs in the TDLNs. This intricate communication network between PSB-MAL, the OMVPSB-MAL, and APCs promoted the efficient presentation of tumor antigens in the tumor periphery and TDLNs. Consequently, there was a notable increase in the infiltration of cytotoxic T lymphocytes (CTLs) into the tumor, triggering potent antitumor immune responses in both melanoma and breast cancer models. This cascade of events resulted in enhanced suppression of tumor metastasis and recurrence, underscoring the robust efficacy of our approach. Our interesting study, harnessing the potential of bacteria and OMVs to redirect tumor antigens for enhanced cancer immunotherapy, provides a promising path toward the development of personalized cancer vaccination strategies.

Aminated yeast β-D-glucan for macrophage-targeted delivery of CpG oligodeoxynucleotides and synergistically enhanced cancer immunotherapy

CpG oligodeoxynucleotides (CpG ODNs) activate immune system and show strong potential in cancer immunotherapy. However, therapeutic efficacy of CpG ODNs is hampered due to rapid nuclease degradation and insufficient cellular uptake. Delivery of CpG ODNs into antigen presenting cells (APCs) is vital to enhance their therapeutic efficacy. Herein, we developed a super-convenient yet efficient strategy for macrophage-targeted delivery of CpG ODNs and synergistically enhanced cancer immunotherapy. Aminated yeast β-D-glucan (NH2-Glu) was simply synthesized through functionalization of β-D-glucan with DETA, which exhibited a dendrimer-like shape with size of about 80 nm. NH2-Glu complexed negatively-charged CpG ODNs. The as-prepared NH2-Glu/CpG complexes were positively charged, uniformly dispersed and exhibited good stability against nuclease degradation. Due to the specific recognition with dectin-1 expressed on macrophages, NH2-Glu/CpG complexes targeted macrophage and exhibited significantly enhanced cellular uptake due to dectin-1-mediated endocytosis. NH2-Glu/CpG complexes showed potent immunostimulatory activity. Contributed by the inherent immunostimulatory and antitumor activity, yeast β-D-glucan functioned synergistically with CpG ODNs in inducing antitumor immunity. NH2-Glu/CpG complexes remarkably inhibited tumor growth without causing toxic effect. In summary, this work provides a facile yet efficient macrophage-targeted CpG ODNs delivery system for cancer immunotherapy.

Remodeling of Tumor Microenvironment by Nanozyme Combined cGAS-STING Signaling Pathway Agonist for Enhancing Cancer Immunotherapy.

Nanozymes and cyclic GMP-AMP synthase (cGAS) the stimulator of interferon genes (STING) signaling pathway, as powerful organons, can remodel the tumor microenvironment (TME) to increase efficacy and overcome drug resistance in cancer immunotherapy. Nanozymes have the potential to manipulate the TME by producing reactive oxygen species (ROS), which lead to positive oxidative stress in tumor cells. Cyclic dinucleotide (2',3'-cGAMP), as a second messenger, exists in the TME and can regulate it to achieve antitumor activity. In this work, Co,N-doped carbon dots (CoNCDs) were used as a model nanozyme to evaluate the properties of the anti-tumor mechanism, and effective inhibition of S180 tumor was achieved. Based on CoNCDs' good biocompatibility and therapeutic effect on the tumor, we then introduced the cGAS-STING agonist, and the combination of the CoNCDs and STING agonist significantly inhibited tumor growth, and no significant systemic toxicity was observed. The combined system achieved the enhanced tumor synergistic immunotherapy through TME reprogramming via the peroxidase-like activity of the CoNCDs and cGAS-STING signaling pathway agonist synergistically. Our work provides not only a new effective way to reprogram TME in vivo, but also a promising synergic antitumor therapy strategy.

Optogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy

The cGAS-STING signaling pathway has emerged as a promising target for immunotherapy development. Here, we introduce a light-sensitive optogenetic device for control of the cGAS/STING signaling to conditionally modulate innate immunity, called ‘light-inducible SMOC-like repeats’ (LiSmore). We demonstrate that photo-activated LiSmore boosts dendritic cell (DC) maturation and antigen presentation with high spatiotemporal precision. This non-invasive approach photo-sensitizes cytotoxic T lymphocytes to engage tumor antigens, leading to a sustained antitumor immune response. When combined with an immune checkpoint blocker (ICB), LiSmore improves antitumor efficacy in an immunosuppressive lung cancer model that is otherwise unresponsive to conventional ICB treatment. Additionally, LiSmore exhibits an abscopal effect by effectively suppressing tumor growth in a distal site in a bilateral mouse model of melanoma. Collectively, our findings establish the potential of targeted optogenetic activation of the STING signaling pathway for remote immunomodulation in mice.

Reinforcing the immunogenic cell death to enhance cancer immunotherapy efficacy.

Immunogenic cell death (ICD) has been a revolutionary modality in cancer treatment since it kills primary tumors and prevents recurrent malignancy simultaneously. ICD represents a particular form of cancer cell death accompanied by production of damage-associated molecular patterns (DAMPs) that can be recognized by pattern recognition receptors (PRRs), which enhances infiltration of effector T cells and potentiates antitumor immune responses. Various treatment methods can elicit ICD involving chemo- and radio-therapy, phototherapy and nanotechnology to efficiently convert dead cancer cells into vaccines and trigger the antigen-specific immune responses. Nevertheless, the efficacy of ICD-induced therapies is restrained due to low accumulation in the tumor sites and damage of normal tissues. Thus, researchers have been devoted to overcoming these problems with novel materials and strategies. In this review, current knowledge on different ICD modalities, various ICD inducers, development and application of novel ICD-inducing strategies are summarized. Moreover, the prospects and challenges are briefly outlined to provide reference for future design of novel immunotherapy based on ICD effect.

Near-Infrared Triggered Self-Accelerating Nanozyme Camouflaged with a Cancer Cell Membrane for Precise Targeted Imaging and Enhanced Cancer Immunotherapy.

Although cancer immunotherapy has made encouraging progress, clinical therapeutic efficiency is often modest due to inadequate immunogenicity and immune resistance. Developing promising nanoagents for simultaneously activating tumor-specific immunity and suppressing immune resistance to achieve efficient immunotherapy is still challenging. Herein, we developed a biomimetic nanozyme consisting of a gold nanorod@mesoporous ceria core-shell scaffold with gold nanoparticle deposition and cancer cell membrane camouflage. The nanozyme exhibited near-infrared (NIR)-enhanced GOx-mimicking activity at high temperatures and performed well under hypoxic environments due to an increased in situ oxygen supply. In cancer cells, the nanozyme induced and amplified hyperthermia by triggering self-accelerating cascade reactions to deplete glucose and inhibiting the expression of heat shock protein under NIR irradiation, which can cause mitochondrial dysfunction and redox balance disruption to activate pyroptosis and elicit a robust immune response. Additionally, the immune checkpoint blockade caused by encapsulated JQ1-mediated PD-L1 downregulation synergistically contributed to excellent immune therapeutic effects. Besides, we demonstrated that cancer cell membrane coating endows the nanozyme targeting ability to tumor. The proposed nanozyme will broaden the application of GOx and have the potential as the nanoplatform for imaging-guided and O2-consuming combined treatments.

DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability

Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70’s cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.

Docetaxel-loaded pH/ROS dual-responsive nanoparticles with self-supplied ROS for inhibiting metastasis and enhancing immunotherapy of breast cancer

BackgroundAlthough stimuli-responsive nanoplatforms were developed to deliver immunogenic cell death (ICD) inducers to enhance cancer immunotherapy, the complete release of ICD inducers into the tumor microenvironment (TME) was limited by the inadequate supplementation of endogenous stimulus (e.g., reactive oxygen species (ROS)). To address this issue, we synthesized a self-responsive nanomaterial with self-supplied ROS, which mainly consists of a ROS responsive moiety HPAP and cinnamaldehyde (CA) as the ROS-generating agent. The endogenous ROS can accelerate the degradation of HPAP in materials to release docetaxel (DTX, an ICD inducer). In intracellular acidic environment, the pH-sensitive acetal was cleaved to release CA. The released CA in turn induces the generation of more ROS through mitochondrial damage, resulting in amplified DTX release. Using this self-cycling and self-responsive nanomaterial as a carrier, DTX-loaded pH/ROS dual-responsive nanoparticles (DTX/FA-CA-Oxi-αCD NPs) were fabricated and evaluated in vitro and in vivo.ResultsIn vitro experiments validated that the NPs could be effectively internalized by FA-overexpressed cells and completely release DTX in acidic and ROS microenvironments to induce ICD effect. These NPs significantly blocked 4T1 cell migration and decreased cell invasion. In vivo experiments demonstrated that the tumor-targeted NPs significantly inhibited tumor growth and blocked tumor metastasis. More importantly, these NPs significantly improved immunotherapy through triggering effector T-cell activation and relieving the immunosuppressive state of the TME.ConclusionsOur results demonstrated that DTX/FA-CA-Oxi-αCD NPs displayed great potential in preventing tumor metastasis, inhibiting tumor growth, and improving the efficacy of anti-PD-1antibody.Graphical

Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy.

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME.

Cordycepin synergizes with CTLA-4 blockade to remodel the tumor microenvironment for enhanced cancer immunotherapy

The strategy of using immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, leading to remarkable clinical outcomes. However, certain cancer types and patient demographics continue to face unique challenges. As a result, it is vital to investigate combination therapies that involve ICIs to boost therapeutic efficacy. Cordycepin, an adenosine derivative composed of adenine and pentose, holds immense promise for treating inflammation and cancer. Our recent research has demonstrated that the combined treatment of cordycepin and the anti-CD47 antibody significantly curtails tumor growth and extends the lifespan of tumor-bearing mice. In the current study, we showed that the combination of cordycepin and CTLA-4 blockade had a profound impact on suppressing tumor growth. We utilized the MC38 and CT26 tumor models to evaluate the therapeutic effect of cordycepin, CTLA-4 blockade, and their combined approach. Flow cytometry results unveiled that cordycepin, when combined with CTLA-4 blockade, considerably augmented the presence of tumor-infiltrating CD8+T cells and diminished the population of Foxp3+Tregs within the tumor microenvironment (TME). Additionally, we employed single-cell analysis to examine the TME’s reconfiguration upon the combined treatment of anti-CTLA-4 and cordycepin. We observed a significant impact on inhibiting tumor growth and substantially extended survival in tumor-bearing mice. Our data also demonstrated an increased proportion of effector CD8+T cells in the combined treatment group compared to all other groups, while exhausted CD8+T cells diminished in the combined group compared to the anti-CTLA-4 treatment alone. In conclusion, our findings supported the idea that combining cordycepin and CTLA-4 blockade could modify the effector and exhaustion status of CD8+T cells, thereby bolstering CD8+T-cell-mediated anti-tumor immunity in the TME. Collectively, our current study successfully established a combination therapeutic strategy utilizing cordycepin and CTLA-4 blockade. This strategy demonstrated a significant synergistic effect against cancer, highlighting its importance in cancer treatment.