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As an evolutionarily conserved DNA-sensing machinery in innate immunity, the cGAS-STING pathway has been reported to play an important role in immune surveillance and tumor suppression. Recent evidence suggests an intriguing tumor- and metastasis-promoting effect of this signaling pathway, either in a cancer cell-autonomous or a cancer cell-nonautonomous, bystander cell-mediated manner. Here, we show a new face of cGAS-STING signaling whose activation in a cancer-cell-autonomous response manner confers drug resistance. Targeted or conventional chemotherapy drug treatment induced cancer cell cytosolic DNA accumulation and triggered subsequent cGAS-STING signaling activation in cancer cell lines and the human cell-derived xenograft tumors. This activation promoted an acquisition and maintenance of drug resistance which was prevented and overcome in vitro and in vivo by blockade of STING signaling. This finding highlights a new face of cGAS-STING signaling and an ability of cancer cells to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress and warrants a caution in combining STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.Statement of significancecGAS-STING signaling has long been recognized as playing a key role in triggering antitumor immunity. We reveal a new face of cGAS-STING signaling and an ability of cancer cells autonomously to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress.

Investigation of novel molecular mechanisms is essential to develop strategies to overcome acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Integrin has been demonstrated as a regulator of cancer progression. The aim of this study was to identify which specific integrins are involved and regulated in acquired resistance to EGFR TKIs in EGFR-mutant lung cancer. The expression levels of integrin subunits were examined in EGFR-mutant lung cancer cells and xenograft tumors with acquired resistance to EGFR TKIs. Manipulation of integrin β3 was performed to explore whether integrin β3 overexpression was associated with TKI resistance, anoikis resistance, EMT, and cancer stemness in resistant lung cancer. To explore the mechanism, TGFβ1 level was examined, and TGFβ1 inhibitor was then used. Integrin β3 was dramatically and consistently overexpressed in acquired gefitinib- or osimertinib-resistant lung cancer in vitro and in vivo. Integrin β3 was also involved in the progression of lung adenocarcinoma. Antagonizing integrin β3 increased the TKI sensitivity and delayed the occurrence of TKI resistance in vitro and in vivo, as well as suppressed proliferation, anoikis resistance, and EMT phenotype in lung cancer cells. Overexpression of integrin β3 was also associated with the enhanced cancer stemness that was acquired in the development of resistance and suppressed by antagonizing integrin β3. Mechanistically, integrin β3 was induced by increased TGFβ1 levels in acquired TKI-resistant lung cancer. Our study identified the TGFβ1/integrin β3 axis as a promising target for combination therapy to delay or overcome acquired resistance to EGFR TKIs in EGFR-mutant lung cancer.

Supplementary Legends and Figures S1-S8 show ITGB3 expression and function in acquired resistance

Supplementary Table from Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma

Supplementary Data from Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities.Significance:Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.

Combine complex equipment collaborative development in military-civilian integration context not only fulfils actual development requirement, but also beneficial to the national economy. Design procedure as first stage of complex equipment military-civilian collaborative development process, select suitable design supplier is significant to whole development process of complex equipment. In order to select suitable design supplier for complex equipment, two aspects done in this paper. One is comprehensive analysis of evaluated influencing factors that affect complex equipment military-civilian collaborative design process, corresponding evaluation indicator constructed and a combination of grey correlation, entropy, DEMATEL (Decision-making Trial and Evaluation Laboratory) and VIKOR analysis theory to obtain grey entropy-DEMATEL-VIKOR, then the combined method is utilized to acquire matching attributes for followed research content. Meanwhile, satisfaction degree for matching side obtained with the help of information aggregation based on power generalized Heronian mean which on the basis of fuzzy preference information. Then, through constructed matching model, suitable design supplier obtained. Finally, a corresponding illustrative example given.

PurposeIndustry practice has shown that technology licensing has an important effect on the R&D cooperation between firms. Different licensing methods will significantly impact a supply chain member's cooperative and price R&D decisions. However, there is scant literature investigating the decision on technology licensing and its impact on a supply chain member's price and cooperative R&D decisions. To address this gap, the authors investigate the R&D cooperation and the technology licensing in a supply chain formed of an original equipment manufacturer (OEM), a contract manufacturer (CM), and a third-party manufacturer which will compete with the OEM when the technology licensing occurs.Design/methodology/approachThe authors investigate two licensing patterns, royalty licensing, fixed fee licensing together with the no licensing, within the R&D cooperative supply chain by developing two three-stage and a two-stage Stackelberg models.FindingsCompare to the no licensing strategy, technology licensing always benefits to the OEM and the society especially when the technology efficiency and the brand power of the third-party manufacturer are more significant; the royalty licensing benefits to the OEM more when the technology efficiency and the brand power of the third-party manufacturer are higher; the fixed fee licensing benefits to the OEM more when the technology efficiency and the brand power of the third-party manufacturer are lower.Practical implicationsThe royalty licensing is more effective for mitigating price competition intensity and helping firms to maintain higher sales margins; the fixed fee licensing induces firms' lower sales margins but increases the firms' sales quantities; in most cases, the fixed fee licensing is optimal from the perspectives of consumer and society, however, the CM's investment intention to the R&D technology with the fixed fee licensing is lower.Originality/valueSo far, different licensing models under the R&D cooperation have not been investigated, and the authors propose two three-stage Stackelberg models with considering the competition caused by technology licensing under the R&D cooperation to deal with the cooperative R&D and technology licensing issues.

Background Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. Results This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. Conclusions The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. Graphical abstract

Chemotherapy is a standard treatment for pediatric acute lymphoblastic leukemia (ALL), which sometimes relapses with chemoresistant features. However, whether acquired drug-resistance mutations in relapsed ALL pre-exist or are induced by treatment remains unknown. Here we provide direct evidence of a specific mechanism by which chemotherapy induces drug-resistance-associated mutations leading to relapse. Using genomic and functional analysis of relapsed ALL we show that thiopurine treatment in mismatch repair (MMR)-deficient leukemias induces hotspot TP53 R248Q mutations through a specific mutational signature (thio-dMMR). Clonal evolution analysis reveals sequential MMR inactivation followed by TP53 mutation in some patients with ALL. Acquired TP53 R248Q mutations are associated with on-treatment relapse, poor treatment response and resistance to multiple chemotherapeutic agents, which could be reversed by pharmacological p53 reactivation. Our findings indicate that TP53 R248Q in relapsed ALL originates through synergistic mutagenesis from thiopurine treatment and MMR deficiency and suggest strategies to prevent or treat TP53-mutant relapse. Zhou and colleagues demonstrate that thiopurine chemotherapy in mismatch repair-deficient ALL cells leads to R248Q TP53 mutations and clonal selection that favors on-treatment ALL relapse and chemoresistance.

Jingyin granules, a marketed antiviral herbal medicine, have been recommended for treating H1N1 influenza A virus infection and Coronavirus disease 2019 (COVID-19) in China. To fight viral diseases in a more efficient way, Jingyin granules are frequently co-administered in clinical settings with a variety of therapeutic agents, including antiviral drugs, anti-inflammatory drugs, and other Western medicines. However, it is unclear whether Jingyin granules modulate the pharmacokinetics of Western drugs or trigger clinically significant herb-drug interactions. This study aims to assess the inhibitory potency of the herbal extract of Jingyin granules (HEJG) against human drug-metabolizing enzymes and to clarify whether HEJG can modulate the pharmacokinetic profiles of Western drug(s) in vivo. The results clearly demonstrated that HEJG dose-dependently inhibited human CES1A, CES2A, CYPs1A, 2A6, 2C8, 2C9, 2D6, and 2E1; this herbal medicine also time- and NADPH-dependently inhibited human CYP2C19 and CYP3A. In vivo tests showed that HEJG significantly increased the plasma exposure of lopinavir (a CYP3A-substrate drug) by 2.43-fold and strongly prolonged its half-life by 1.91-fold when HEJG (3 g/kg) was co-administered with lopinavir to rats. Further investigation revealed licochalcone A, licochalcone B, licochalcone C and echinatin in Radix Glycyrrhizae, as well as quercetin and kaempferol in Folium Llicis Purpureae, to be time-dependent CYP3A inhibitors. Collectively, our findings reveal that HEJG modulates the pharmacokinetics of CYP substrate-drug(s) by inactivating CYP3A, providing key information for both clinicians and patients to use herb-drug combinations for antiviral therapy in a scientific and reasonable way.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths, characterized by highly hypoxic tumor microenvironment. Hypoxia-inducible factor-1α (HIF-1α) is a major regulator involved in cellular response to changes of oxygen levels, supporting the adaptation of tumor cells to hypoxia. Bruceine D (BD) is an isolated natural quassinoid with multiple anti-cancer effects. Here, we identified BD could significantly inhibit the HIF-1α expression and its subsequently mediated HCC cell metabolism. Using biophysical proteomics approaches, we identified inhibitor of β-catenin and T-cell factor (ICAT) as the functional target of BD. By targeting ICAT, BD disrupted the interaction of β-catenin and ICAT, and promoted β-catenin degradation, which in turn induced the decrease of HIF-1α expression. Furthermore, BD could inhibit HCC cells proliferation and tumor growth in vivo, and knockdown of ICAT substantially increased resistance to BD treatment in vitro. Our data highlight the potential of BD as a modulator of β-catenin/HIF-1α axis mediated HCC metabolism., Graphical abstract Bruceine D disrupted the direct interaction between ICAT and β-catenin, inducing β-catenin degradation, which in turn induced the decrease of HIF-1α expression and its subsequently mediated HCC cell metabolism.Image 1

Peptide stapling chemistry represents an attractive strategy to promote the clinical translation of protein epitope mimetics, but its use has not been applied to natural cytotoxic peptides (NCPs) to produce new oncolytic peptides. Based on a wasp venom peptide, a series of stapled anoplin peptides (StAnos) were prepared. The optimized stapled Ano-3/3s were shown to be protease-resistant and exerted superior tumor cell-selective cytotoxicity by rapid membrane disruption. In addition, Ano-3/3s induced tumor ablation in mice through the direct oncolytic effect and subsequent stimulation of immunogenic cell death. This synergistic oncolytic-immunotherapy effect is more remarkable on melanoma than on triple-negative breast cancer in vivo. The efficacies exerted by Ano-3/3s on melanoma were further characterized by CD8+ T cell infiltration, and the addition of anti-CD8 antibodies diminished the long-term antitumor effects. In summary, these results support stapled peptide chemistry as an advantageous method to enhance the NCP potency for oncolytic therapy.

Two-sided matching is a common research topic in our everyday life like marriage problem between men and women, schools and students. However, from the industrial perspective, the matching problem for complex equipment is a special research direction that needs professional participants that involve in the complex equipment production process. In this paper, a two-sided matching model for complex equipment production on the military–civilian integration platform is constructed that considers the reference satisfaction, and the reference satisfaction is firstly proposed which originates from operation management field. Moreover, the main influencing factors for complex equipment production are analyzed based on combined evaluation methods. The combined evaluation methods utilized in this research, one is DEMATEL (Decision Making Trial and Evaluation) method and the other is Grey–TOPSIS (Technique for Order Preference by Similarity for an Ideal Solution) method, are employed to acquire the joint importance results of the main analyzed influencing factors. The analyzed influencing factors are based on the evaluation indicators established in the evaluation indicator system for complex equipment production on the military–civilian merging platform, and the evaluation indicators are collected from relevant exist research. Then, suppliers and the manufacturers involved in the production of complex equipment give preference information to each other, and preference information is given on the basis of comprehensive analysis of the analyzed influencing factors which is by the aid of the aforementioned DEMATEL–Grey–TOPSIS analysis; meanwhile, the real satisfaction value of the suppliers and the manufacturers is obtained based on the preference value; then, the comprehensive reference satisfaction value could be obtained from the combination of the real satisfaction value and the expected satisfaction (real satisfaction value and disappointed satisfaction value), through aforementioned could we build a two-sided matching model for complex equipment on the military–civilian integration platform. Finally, we use a numerical example to illustrate the whole process about supplier–manufacturer matching for complex equipment production on the military–civilian integration platform.

Background Currently, there is no cure for Alzheimer’s disease (AD). Therapeutics that can modify the early stage of AD are urgently needed. Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase (AEP). Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD. However, more than 90% of AD cases are age-related sporadic AD rather than hereditary AD. The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown. Methods The senescence-accelerated mouse prone 8 (SAMP8) was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,: δ-secretase inhibitor 11. Activation of AEP was determined by enzymatic activity assay. Concentration of soluble amyloid β (Aβ) in the brain was determined by ELISA. Morris water maze test was performed to assess the learning and memory-related cognitive ability. Pathological changes in the brain were explored by morphological and western blot analyses. Results The enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the age-matched SAMR1 mice. The half maximal inhibitory concentration (IC50) for δ-secretase inhibitor 11 to inhibit AEP in vitro is was around 150 nM. Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity, reduced the generation of Aβ1–40/42 and ameliorated memory loss. The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation, but also attenuated neuroinflammation in the form of microglial activation. Moreover, treatment with δ-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain. Conclusions Pharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD. The up-regulated AEP in the brain could be a promising target for early treatment of AD. The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.

Covering: up to 2020 Treatment resistance and drug-induced refractory malignancies pose significant challenges for current chemotherapy drugs. There have been increasing research efforts aimed at developing novel chemotherapeutics, especially from natural products and related derivatives. Natural cytotoxic peptides, an emerging source of chemotherapeutics, have exhibited the advantage of overcoming drug resistance and displayed broad-spectrum antitumor activities in the clinic. This highlight examines the increasingly popular cytotoxic peptides from isolated natural products. In-depth review of several peptides provides examples for how this novel strategy can lead to the improved anti-tumor effects. The mechanisms and current application of representative natural cytotoxic peptides (NCPs) have also been discussed, with a particular focus on future directions for interdisciplinary research.

Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.

Tumor hypoxic stress after photodynamic therapy (PDT) will be inevitably exacerbated by the vascular blocking effects and oxygen consumption in the tumor microenvironment (TME) which usually leads to compromised efficacy and clinical performance. Increasing evidence links the hypoxia induced up-regulation of hypoxia inducible factor 1α (HIF-1α) with immunosuppressive TME, including the polarization of M2 phenotype tumor associated macrophages (TAMs), which promote the recurrence and metastasis. Here, we reported NIR-triggered core-satellite upconverting nanoparticles (CSNPs) with curcumin (Cur) embedded as a difunctional photosensitizer, which could realize PDT in deep tumors with long excitation wavelength (980 nm) and reverse the immunosuppressive TME induced by up-regulated HIF-1α at the same time. This Cur-loaded CSNPs (Cur-CSNPs)-mediated PDT could successfully induce the immunogenic cell death (ICD) of triple negative breast cancer (TNBC) cell lines (4T1 and MDA-MB-231) in vitro and repolarize the 4T1 cells co-cultured TAMs from pro-tumor M2 to the anti-tumor M1 phenotype. Furthermore, Cur-CSNPs-mediated PDT could suppress the 4T1 tumor growth in primary and distant sites through the synergistic immunotherapeutic effects in vivo by priming M1 type TAMs and CD4+/CD8+ T cells' infiltration. Our data highlight the novel application of CSNPs-embedded Cur as a difunctional photosensitizer to enhance the anti-tumor efficacy of PDT.

Despite the various mechanisms that involved in the pathogenesis of Alzheimer's disease (AD), neuronal damage and synaptic dysfunction are the key events leading to cognition impairment. Therefore, neuroprotection and neurogenesis would provide essential alternatives to the rescue of AD cognitive function. Here we demonstrated that extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs-derived EVs, abbreviated as EVs) entered the brain quickly and efficiently following intranasal administration, and majorly accumulated in neurons within the central nervous system (CNS). Proteomics analysis showed that EVs contained multiple proteins possessing neuroprotective and neurogenesis activities, and neuronal RNA sequencing showed genes enrichment in neuroprotection and neurogenesis following the treatment with EVs. As a result, EVs exerted powerful neuroprotective effect on Aβ1-42 oligomer or glutamate-induced neuronal toxicity, effectively ameliorated neurologic damage in the whole brain areas, remarkably increased newborn neurons and powerfully rescued memory deficits in APP/PS1 transgenic mice. EVs also reduced Aβ deposition and decreased microglia activation although in a less extent. Collectively, here we provide direct evidence that ADSCs-derived EVs may potentially serve as an alternative for AD therapy through alleviating neuronal damage and promoting neurogenesis.

Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.

The secondary damage in traumatic brain injury (TBI) can lead to lifelong disabilities, bringing enormous economic and psychological burden to patients and their families. Mitochondria, as the core mediator of the secondary injury cascade reaction in TBI, is an important target to prevent the spread of cell death and dysfunction. Thus, therapeutics that can accumulate at the damaged sites and subsequently rescue the functions of mitochondria would largely improve the outcome of TBI. Cyclosporine A (CsA), which can maintain the integrity of mitochondrial function, is among the most promising neuroprotective therapeutics for TBI treatment. However, the clinical application of CsA in TBI is largely hindered because of its poor access to the targets. Here, to realize targeted intracellular CsA delivery, we designed a lipoprotein biomimetic nanocarrier by incorporating CsA in the core and decorating a matrix metalloproteinase-9 activatable cell-penetrating peptide onto the surface of the lipoprotein-mimic nanocarrier. This CsA-loaded tailored reconstituted lipoprotein efficiently accumulated at the damaged brain sites, entered the target cells, bound to the membrane of mitochondria, more efficiently reduced neuronal damage, alleviated neuroinflammation, and rescued memory deficits at the dose 1/16 of free CsA in a controlled cortical impact injury mice model. The findings provide strong evidence that the secondary damages in TBI can be well controlled through targeted CsA delivery and highlight the potential of a lipoprotein biomimetic nanocarrier as a flexible nanoplatform for the management of TBI.

Liposomal drug delivery for cancer therapy can be limited due to drug leakage in circulation. Here, we develop a new method to enhance the stability of actively loaded liposomal doxorubicin (DOX) through embedding a stiff nanobowl in the liposomal water cavity. Nanobowl-supported liposomal DOX (DOX@NbLipo) resists the influence of plasma protein and blood flow shear force to prevent drug leakage. This approach yields improved drug delivery to tumor sites and enhanced antitumor efficacy. Compared to alternative methods of modifying liposome surface and composition for stability, this approach designs a physical support for an all-aqueous nanoliposomal cavity. Nanobowl stabilization of liposomes is a simple and effective method to improve carrier stability and drug delivery.

In view of the multiple pathological hallmarks of tumors, nanosystems for the sequential delivery of various drugs whose targets are separately located inside and outside tumor cells are desired for improved cancer therapy. However, current sequential delivery is mainly achieved through enzyme- or acid-dependent degradation of the nanocarrier, which would be influenced by the heterogeneous tumor microenvironment, and unloading efficiency of the drug acting on the target outside tumor cells is usually unsatisfactory. Here, a light-triggered sequential delivery strategy based on a liposomal formulation of doxorubicin (DOX)-loaded small-sized polymeric nanoparticles (DOX-NP) and free sunitinib in the aqueous cavity, is developed. The liposomal membrane is doped with photosensitizer porphyrin-phospholipid (PoP) and hybridized with red blood cell membrane to confer biomimetic features. Near-infrared light-induced membrane permeabilization triggers the "ultrafast" and "thorough" release of sunitinib (100% release in 5 min) for antiangiogenic therapy and also myeloid-derived suppressor cell (MDSC) inhibition to reverse the immunosuppressive tumor environment. Subsequently, the small-sized DOX-NP liberated from the liposomes is more easily uptaken by tumor cells for improved immunogenic chemotherapy. RNA sequencing and immune-related assay indicates therapeutic immune enhancement. This light-triggered sequential delivery strategy demonstrates the potency in cancer multimodal therapy against multiple targets in different spatial positions in tumor microenvironment.

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities. Significance: Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.