NKAIN1, as an oncogene, promotes the proliferation and metastasis of breast cancer, affecting its prognosis.

Na, K-ATPase interaction (NKAIN) is a transmembrane protein family, which can interact with Na, K-ATPase ß1 subunit. NKAIN1 plays an important role in alcohol-dependent diseases such as endometrial and prostate cancers. However, the relationship between NKAIN1 and human breast cancer has not been studied. Hence, this study aimed to explore the relationship between NKAIN1 expression and breast cancer. Data used in this study were mainly from the Cancer Genome Atlas, including differential expression analysis, Kaplan-Meier survival analysis, receiver operating characteristic curve analysis, multiple Cox regression analysis, co-expression gene analysis, and gene set enrichment analysis. Analyses were performed using reverse transcription-quantitative polymerase chain reaction, western blot analysis, and immunohistochemistry on 46 collected samples. The knockdown or overexpression of NKAIN1 in vitro in MCF-7 and MDA-MB-231 cell lines altered the proliferation and migration abilities of tumor cells. In vivo experiments further confirmed that NKAIN1 knockdown effectively inhibited the proliferation and migration of cancer cells. Therefore, our study identified NKAIN1 as an oncogene that is highly expressed in breast cancer tissues. The findings highlight the potential of NKAIN1 as a molecular biomarker of breast cancer.

Sequential Therapy of Acute Kidney Injury with a DNA Nanodevice.

The high demand for acute kidney injury (AKI) therapy calls the development of multifunctional nanomedicine for renal management with programmable pharmacokinetics. Here, we developed a renal-accumulating DNA nanodevice with exclusive kidney retention for longitudinal protection of AKI in different stages in a renal ischemia-reperfusion (I/R) model. Due to the prolonged kidney retention time (>12 h), the ROS-sensitive nucleic acids of the nanodevice could effectively alleviate oxidative stress by scavenging ROS in stage I, and then the anticomplement component 5a (aC5a) aptamer loaded nanodevice could sequentially suppress the inflammatory responses by blocking C5a in stage II, which is directly related to the cytokine storm. This sequential therapy provides durable and pathogenic treatment of kidney dysfunction based on successive pathophysiological events induced by I/R, which holds great promise for renal management and the suppression of the cytokine storm in more broad settings including COVID-19.

Unraveling Cell-Type-Specific Targeted Delivery of Membrane-Camouflaged Nanoparticles with Plasmonic Imaging.

Cell-membrane-camouflaged nanoparticles (CMC-NPs) have been increasingly exploited to develop various therapeutic tools due to their high biocompatibility and cell-type-specific tumor-targeting properties. However, the molecular mechanism of CMC-NPs for homotypic targeting remains elusive. Here, we develop a plasmonic imaging method by coating gold nanoparticles (AuNPs) with cancer cell membranes and perform plasmonic imaging of the interactions between CMC-NPs and living cells at the single-cell level. Quantitative analysis of CMC-NPs in a different clustering status reveals that the presence of cell membranes on CMC-NPs results in a 7-fold increase in homotypic cell delivery and nearly 2 orders of magnitude acceleration of the intracellular agglomeration process. Significantly, we identify that integrin αvß3, a cell surface receptor abundantly expressed in tumor cells, is critical for the selective cell recognition of CMC-NPs. We thus establish a single-cell plasmonic imaging platform for probing NP-cell interactions, which sheds new light on the therapeutic applications of CMC-NPs.

SUMO regulates somatic cyst stem cell maintenance and directly targets the Hedgehog pathway in adult Drosophila testis.

SUMO (Small ubiquitin-related modifier) modification (SUMOylation) is a highly dynamic post-translational modification (PTM) that plays important roles in tissue development and disease progression. However, its function in adult stem cell maintenance is largely unknown. Here, we report the function of SUMOylation in somatic cyst stem cell (CySC) self-renewal in adult Drosophila testis. The SUMO pathway cell-autonomously regulates CySC maintenance. Reduction of SUMOylation promotes premature differentiation of CySCs and impedes the proliferation of CySCs, which leads to a reduction in the number of CySCs. Consistent with this, CySC clones carrying a mutation of the SUMO-conjugating enzyme are rapidly lost. Furthermore, inhibition of the SUMO pathway phenocopies disruption of the Hedgehog (Hh) pathway, and can block the proliferation of CySCs induced by Hh activation. Importantly, the SUMO pathway directly regulates the SUMOylation of Hh pathway transcription factor Cubitus interruptus (Ci), which is required for promoting CySC proliferation. Thus, we conclude that SUMO directly targets the Hh pathway and regulates CySC maintenance in adult Drosophila testis.

Coop functions as a corepressor of Pangolin and antagonizes Wingless signaling.

Wingless (Wg) signaling regulates expression of its target genes via Pangolin and Armadillo, and their interacting cofactors. In the absence of Wg, Pangolin mediates transcriptional repression. In the presence of Wg, Pangolin, Armadillo, and a cohort of coactivators mediate transcriptional activation. Here we uncover Coop (corepressor of Pan) as a Pangolin-interacting protein. Coop and Pangolin form a complex on DNA containing a Pangolin/TCF-binding motif. Overexpression of Coop specifically represses Wg target genes, while loss of Coop function causes derepression. Finally, we show that Coop antagonizes the binding of Armadillo to Pangolin, providing a mechanism for Coop-mediated repression of Wg target gene transcription.

In†Situ Spatial Complementation of Aptamer-Mediated Recognition Enables Live-Cell Imaging of Native RNA Transcripts in Real Time.

Direct cellular imaging of the localization and dynamics of biomolecules helps to understand their function and reveals novel mechanisms at the single-cell resolution. In contrast to routine fluorescent-protein-based protein imaging, technology for RNA imaging remains less well explored because of the lack of enabling technology. Herein, we report the development of an aptamer-initiated fluorescence complementation (AiFC) method for RNA imaging by engineering a green fluorescence protein (GFP)-mimicking turn-on RNA aptamer, Broccoli, into two split fragments that could tandemly bind to target mRNA. When genetically encoded in cells, endogenous mRNA molecules recruited Split-Broccoli and brought the two fragments into spatial proximity, which formed a fluorophore-binding site in situ and turned on fluorescence. Significantly, we demonstrated the use of AiFC for high-contrast and real-time imaging of endogenous RNA molecules in living mammalian cells. We envision wide application and practical utility of this enabling technology to in vivo single-cell visualization and mechanistic analysis of macromolecular interactions.

Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. An alternative strategy is to target cells, such as tumour-infiltrating macrophages, in the HCC tumour microenvironment. The CCL2/CCR2 axis is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including HCC. We investigated the feasibility of CCL2/CCR2 as a therapeutic target against HCC. DESIGN: CCL2 expression was analysed in two independent HCC cohorts. Growth of three murine HCC cells was evaluated in an orthotopic model, a postsurgical recurrence model and a subcutaneous model in mice after blocking CCL2/CCR2 axis by a novel CCR2 antagonist or knocking out of host CCR2. In vivo macrophage or T cell depletion and in vitro cell coculture were further conducted to investigate CCL2/CCR2-mediated crosstalk between tumour-associated macrophages (TAMs) and tumour cells. RESULT: CCL2 is overexpressed in human liver cancers and is prognostic for patients with HCC. Blockade of CCL2/CCR2 signalling with knockout of CCR2 or with a CCR2 antagonist inhibits malignant growth and metastasis, reduces postsurgical recurrence, and enhances survival. Further, therapeutic blocking of the CCL2/CCR2 axis inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs, resulting in reversal of the immunosuppression status of the tumour microenvironment and activation of an antitumorous CD8+ T cell response. CONCLUSIONS: In patients with liver cancer, CCL2 is highly expressed and is a prognostic factor. Blockade of CCL2/CCR2 signalling suppresses murine liver tumour growth via activating T cell antitumour immune response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.

Organelle-Specific Triggered Release of Immunostimulatory Oligonucleotides from Intrinsically Coordinated DNA-Metal-Organic Frameworks with Soluble Exoskeleton.

DNA has proven of high utility to modulate the surface functionality of metal-organic frameworks (MOFs) for various biomedical applications. Nevertheless, current methods for preparing DNA-MOF nanoparticles rely on either inefficient covalent conjugation or specific modification of oligonucleotides. In this work, we report that unmodified oligonucleotides can be loaded on MOFs with high density (∼2500 strands/particle) via intrinsic, multivalent coordination between DNA backbone phosphate and unsaturated zirconium sites on MOFs. More significantly, surface-bound DNA can be efficiently released in either bulk solution or specific organelles in live cells when free phosphate ions are present. As a proof-of-concept for using this novel type of DNA-MOFs in immunotherapy, we prepared a construct of immunostimulatory DNA-MOFs (isMOFs) by intrinsically coordinating cytosine-phosphate-guanosine (CpG) oligonucleotides on biocompatible zirconium MOF nanoparticles, which was further armed by a protection shell of calcium phosphate (CaP) exoskeleton. We demonstrated that isMOFs exhibited high cellular uptake, organelle specificity, and spatiotemporal control of Toll-like receptors (TLR)-triggered immune responses. When isMOF reached endolysosomes via microtubule-mediated trafficking, the CaP exoskeleton dissolved in the acidic environment and in situ generated free phosphate ions. As a result, CpG was released from isMOFs and stimulated potent immunostimulation in living macrophage cells. Compared with naked CpG-MOF, isMOFs exhibited 83-fold up-regulation in stimulated secretion of cytokines. We thus expect this isMOF design with soluble CaP exoskeleton and an embedded sequential "protect-release" program provides a highly generic approach for intracellular delivery of therapeutic nucleic acids.

Systematic network assessment of the carcinogenic activities of cadmium.

Cadmium has been defined as type I carcinogen for humans, but the underlying mechanisms of its carcinogenic activity and its influence on protein-protein interactions in cells are not fully elucidated. The aim of the current study was to evaluate, systematically, the carcinogenic activity of cadmium with systems biology approaches. From a literature search of 209 studies that performed with cellular models, 208 proteins influenced by cadmium exposure were identified. All of these were assessed by Western blotting and were recognized as key nodes in network analyses. The protein-protein functional interaction networks were constructed with NetBox software and visualized with Cytoscape software. These cadmium-rewired genes were used to construct a scale-free, highly connected biological protein interaction network with 850 nodes and 8770 edges. Of the network, nine key modules were identified and 60 key signaling pathways, including the estrogen, RAS, PI3K-Akt, NF-κB, HIF-1α, Jak-STAT, and TGF-ß signaling pathways, were significantly enriched. With breast cancer, colorectal and prostate cancer cellular models, we validated the key node genes in the network that had been previously reported or inferred form the network by Western blotting methods, including STAT3, JNK, p38, SMAD2/3, P65, AKT1, and HIF-1α. These results suggested the established network was robust and provided a systematic view of the carcinogenic activities of cadmium in human.

Physical and biochemical insights on DNA structures in artificial and living systems.

CONSPECTUS: Highly specific DNA base-pairing is the basis for both fulfilling its genetic role and constructing novel nanostructures and hybrid conjugates with inorganic nanomaterials (NMs). There exist many remarkable differences in the physical properties of single-stranded (ss) and double-stranded (ds) DNA, which play important roles in regulation of biological processes in nature. Rapid advances in nanoscience and nanotechnology pose new questions on how DNA and DNA structures interact with inorganic nanomaterials or cells and animals, which should be important for their biological and biomedical applications. In this Account, we intend to provide an overview on many facets of DNA and DNA structures in artificial and living systems, with the focus on their properties and functions at the interfaces of inorganic nanomaterials and biological systems. ssDNA, dsDNA, and DNA nanostructures interact with NMs in different ways. In particular, gold nanoparticles and graphene oxide exhibit strikingly different affinity toward ssDNA and dsDNA. Such binding differences can be coupled with optical properties of NMs. For example, DNA hybridization can effectively modulate the plasmonic and catalytic properties of gold nanoparticles. By exploitation of these interactions, there have been many ways for sensitive transduction of biomolecular recognition for various sensing applications. Alternatively, modulation of the properties of DNA and DNA structures with NMs has led to new tools for genetic analysis including genotyping and haplotyping. Self-assembled DNA nanostructures have emerged as a new type of NMs with pure biomolecules. These nanostructures can be designed in one, two, or three dimensions with various sizes, shapes, and geometries. They also have characteristics of uniform size, precise addressability, excellent water solubility, and biocompatibility. These nanostructures provide a new toolbox for biophysical studies with unparalleled advantages, for example, NMR-based protein structure determination and single-molecule studies. Also importantly, DNA nanostructures have proven highly useful in various applications including biological detection, bioreactors, and nanomedicine. In particular, DNA nanostructures exhibit high cellular permeability, a property that is not available for ssDNA and dsDNA, which is required for their drug delivery applications. DNA and DNA structures can also form hybrids with inorganic NMs. Notably, DNA anchored at the interface of inorganic NMs behaves differently from that at the macroscopic interface. Several types of DNA-NM conjugates have exerted beneficial effects for bioassays and in vitro translation of proteins. Even more interestingly, hybrid nanoconjugates demonstrate distinct properties under the context of biological systems such as cultured cells or animal models. These unprecedented properties not only arouse great interest in studying such interfaces but also open new opportunities for numerous applications in artificial and living systems.

Target-responsive, DNA nanostructure-based E-DNA sensor for microRNA analysis.

Because of the short size and low abundance of microRNAs, it is challenging to develop fast, inexpensive, and simple biosensors to detect them. In this work, we have demonstrated a new generation (the third generation) of E-DNA sensor for the sensitive and specific detection of microRNAs. Our third generation of E-DNA sensor can sensitively detect microRNA target (microRNA-141) as low as 1 fM. The excellent specificity has been demonstrated by its differential ability to the highly similar microRNA analogues. In our design, the use of DNA tetrahedron ensures the stem-loop structure in well controlled density with improved reactivity. The regulation of the thermodynamic stability of the stem-loop structure decreases the background signal and increases the specificity as well. The enzymes attached bring the electrocatalytic signal to amplify the detection. The combination of these effects improves the sensitivity of the E-DNA sensor and makes it suitable to the microRNA detection. Finally, our third generation of E-DNA sensor is generalizable to the detection of other micro RNA targets (for example, microRNA-21).

Long-term effects of nanoparticles on nutrition and metabolism.

Nanoparticles have shown great potential in biological and biomedical applications due to their distinct physical and chemical properties. In the meanwhile, the biosafety of nanoparticles has also raised intense concerns worldwide. To address such concerns, great efforts have been made to examine short-term effects of nanoparticles on cell survival and proliferation. More recently, exploration of long-term effects of nanomaterials, particularly those with promising biomedical applications in vivo, has aroused significant interest. For example, gold nanoparticles (AuNPs) are generally considered non-toxic to cell growth, whereas recent studies suggest that AuNPs might have long-term effects on cellular metabolism and energy homeostasis. In this Review, recent advances in this direction are summarized. Further, possible mechanisms under which nanoparticles regulate metabolic signaling pathways, potential long-term effects on cellular anabolic or catabolic processes, and their implications in human health and metabolic disorders are discussed.

Online water vapor removal membrane inlet mass spectrometer for high-sensitivity detection of dissolved methane.

Underwater mass spectrometry is characterized by excellent consistency, strong specificity, and the ability to simultaneously detect multiple substances, making it a valuable tool in research fields such as aquatic ecosystems, hydrothermal vents, and the global carbon cycle. Nevertheless, current underwater mass spectrometry encounters challenges stemming from the high-water vapor content, constituting proportions of nearly 90%. This results in issues such as peak overlap, interference with peak height, decreased ionization efficiency and, consequently, make it difficult to achieve low detection limits for extremely low concentrations of gases, such as methane, and impede the detection of background CH4 levels. In this study, we optimized the design of the sampling gas path and developed a high gas-tightness, high pressure-resistant membrane inlet system, coupled with a small-volume, low-power online water vapor removal system. This innovation efficiently eliminates water vapor while maintaining a high permeation flux of the target gases. By elevating the vacuum level to the order of 1E-6 Torr, the ionization efficiency and detection performance were improved. Based on this, we created an online water vapor removal membrane inlet mass spectrometer and conducted experimental research. Results indicated that the water removal efficiency approached 100%, and the vacuum level was elevated by more than 2 orders of magnitude. The detection limit for CH4 increased from over 600 nmol/L to 0.03 nmol/L, representing an improvement of over 4 orders of magnitude, and reaching the level of detecting background CH4 signals in deep-sea and lakes. Furthermore, the instrument exhibited excellent responsiveness and tracking capability to concentration changes on the second scale, enabling in situ analysis of rapidly changing concentration scenarios.

Unzippable Siamese Nanoparticles for Programmed Two-Stage Cancer Immunotherapy.

Epigenetic drugs (epi-drugs) can destruct cancer cells and initiate both innate and adaptive immunity, yet they have achieved very limited success in solid tumors so far, partly attributing to their concurrent induction of the myeloid-derived suppressor cell (MDSC) population. Here, dissociable Siamese nanoparticles (SIANPs) are developed for tumor cell-targeted delivery of epi-drug CM-272 and MDSC-targeted delivery of small molecule inhibitor Ibrutinib. The SIANPs are assembled via interparticle DNA annealing and detached via tumor microenvironment-triggered strand separation. Such binary regulation induces endogenous retrovirus expression and immunogenic cell death in tumor cells while restraining the immunosuppressive effects of MDSCs, and synergistically promotes dendritic cell maturation and CD8+ T cell activation for tumor inhibition. Significantly, immune microenvironment remodeling via SIANPs further overcomes tumor resistance to immune checkpoint blockade therapy. This study represents a two-pronged approach for orchestrating immune responses, and paves a new way for employing epi-drugs in cancer immunotherapy.

Online inspection of blackheart in potatoes using visible-near infrared spectroscopy and interpretable spectrogram-based modified ResNet modeling.

Introduction: Blackheart is one of the most common physiological diseases in potatoes during storage. In the initial stage, black spots only occur in tissues near the potato core and cannot be detected from an outward appearance. If not identified and removed in time, the disease will seriously undermine the quality and sale of theentire batch of potatoes. There is an urgent need to develop a method for early detection of blackheart in potatoes. Methods: This paper used visible-near infrared (Vis/NIR) spectroscopy to conduct online discriminant analysis on potatoes with varying degrees of blackheart and healthy potatoes to achieve real-time detection. An efficient and lightweight detection model was developed for detecting different degrees of blackheart in potatoes by introducing the depthwise convolution, pointwise convolution, and efficient channel attention modules into the ResNet model. Two discriminative models, the support vector machine (SVM) and the ResNet model were compared with the modified ResNet model. Results and discussion: The prediction accuracy for blackheart and healthy potatoes test sets reached 0.971 using the original spectrum combined with a modified ResNet model. Moreover, the modified ResNet model significantly reduced the number of parameters to 1434052, achieving a substantial 62.71% reduction in model complexity. Meanwhile, its performance was evidenced by a 4.18% improvement in accuracy. The Grad-CAM++ visualizations provided a qualitative assessment of the model's focus across different severity grades of blackheart condition, highlighting the importance of different wavelengths in the analysis. In these visualizations, the most significant features were predominantly found in the 650-750 nm range, with a notable peak near 700 nm. This peak was speculated to be associated with the vibrational activities of the C-H bond, specifically the fourth overtone of the C-H functional group, within the molecular structure of the potato components. This research demonstrated that the modified ResNet model combined with Vis/NIR could assist in the detection of different degrees of black in potatoes.

Dismantlable Coronated Nanoparticles for Coupling the Induction and Perception of Immunogenic Cell Death.

Therapy-induced immunogenic cell death (ICD) can initiate both innate and adaptive immune responses for amplified anti-tumor efficacy. However, dying cell-released ICD signals are prone to being sequestered by the TIM-3 receptors on dendritic cell (DC) surfaces, preventing immune surveillance. Herein, dismantlable coronated nanoparticles (NPs) are fabricated as a type of spatiotemporally controlled nanocarriers for coupling tumor cell-mediated ICD induction to DC-mediated immune sensing. These NPs are loaded with an ICD inducer, mitoxantrone (MTO), and wrapped by a redox-labile anti-TIM-3 (αTIM-3) antibody corona, forming a separable core-shell structure. The antibody corona disintegrates under high levels of extracellular reactive oxygen species in the tumor microenvironment, exposing the MTO-loaded NP core for ICD induction and releasing functional αTIM-3 molecules for DC sensitization. Systemic administration of the coronated NPs augments DC maturation, promotes cytotoxic T cell recruitment, enhances tumor susceptibility to immune checkpoint blockade, and prevents the side effects of MTO. This study develops a promising nanoplatform to unleash the potential of host immunity in cancer therapy.

Case report: Composite mantle cell lymphoma and classical Hodgkin lymphoma.

Composite mantle cell lymphoma and classical Hodgkin lymphoma is very rare and the actual origin of it is still unclear. Here we reported a new case of composite mantle cell lymphoma and classical Hodgkin lymphoma and analyzed its molecular changes. Eight mutations were identified in its Hodgkin component through next-generation sequencing. In addition, we reviewed the published cases of composite mantle cell lymphoma and classical Hodgkin lymphoma and summarized the molecular changes of reported cases as well as the current case to explore the possible pathway of histogenesis.

Perturbation of intestinal stem cell homeostasis and radiation enteritis recovery via dietary titanium dioxide nanoparticles.

Small intestinal health and enteritis incidence are tightly coupled to the homeostasis of intestinal stem cells (ISCs), which are sensitive to dietary alterations. However, little is known about the impact of food additives on ISC pool. Here, we demonstrate that chronic exposure to low-dose TiO2 NPs, a commonly used food additive, significantly hampers primary human and mouse ISC-derived organoid formation and growth by specifically attenuating Wnt signal transduction. Mechanistically, TiO2 NPs alter the endocytic trafficking of the Wnt receptor LRP6 and prevent the nuclear entry of ß-catenin. Notably, dietary TiO2 NPs elicit modest chronic stress in healthy intestines and considerably impede the recovery of radiation enteritis by perturbing the homeostasis of ISCs in vivo. Our results identify a health concern of TiO2 NP exposure on ISC homeostasis and radiation enteritis recovery. These findings suggest extra precaution during the treatment of radiation enteritis and provide new insights into food additive-ISC interaction.

Composite Hydrogel for Spatiotemporal Lipid Intervention of Tumor Milieu.

Induction of immunogenic cell death (ICD) plays crucial roles in cancer immunotherapy, whereas its efficacy is severely compromised by redundant antioxidant defenses in cancer cells and aberrant lipid metabolism in immunosuppressive cell populations. In this work, it is found that hollow mesoporous CuS nanoparticles (NPs) possess an intrinsic capacity of inhibiting glutathione peroxidase 4 (GPX4). When loaded with an inhibitor of the ferroptosis suppressor protein 1 (FSP1), these NPs block two parallel redox systems and cooperate with near-infrared irradiation to reinforce ICD. A hydrogel co-delivering cancer-cell-targeting CuS NPs and immunosuppressive-cell-targeting sulfo-N-succinimidyl oleate (SSO) for spatiotemporal lipid intervention i further fabricated. While the CuS NPs augment ICD via synergistic lipid peroxidation, SSO reinstates immune perception via lipid metabolic reprogramming, thereby coordinately triggering robust innate and adaptive immunity to restrain tumor growth, relapse, and metastasis. This study provides an immunometabolic therapy via orchestrated lipid modulation in the tumor milieu.

Targeted Reprogramming of Vitamin B3 Metabolism as a Nanotherapeutic Strategy towards Chemoresistant Cancers.

Cancer-associated fibroblasts (CAFs) promote cancer stem cell (CSC)-mediated chemoresistance and immunosuppressive tumor microenvironment. However, direct depletion of CAFs may increase cancer invasiveness and metastasis. As a generalized strategy against chemoresistant cancers, Gemini-like homotypic targeting nanoparticles (NPs) are designed for two-pronged CAF transformation and cancer cell elimination. The CAF-targeted NPs couple vitamin B3 metabolic reprogramming to epigenetic modulation of secreted pro-stemness and immunosuppressive factors, thereby diminishing CSC and suppressive immune cell populations to enhance cancer cell drug susceptibility and cytotoxic T cell infiltration. In mouse models of breast, liver, pancreatic and colorectal cancers that are resistant to their respective first-line chemotherapeutics, a single dose of hydrogel co-delivering the Gemini-like NPs can rehabilitate chemosensitivity, induce immune activation, and achieve tumor regression. Moreover, it stimulates robust T cell memory for long-term protection against tumor rechallenge. This study thus represents an innovative approach with broad applicability for overcoming cancer chemoresistance.