Female Alzheimer's disease (AD) patients display greater cognitive deficits and worse AD pathology as compared to male AD patients. In this study, we found that conditional knockout (cKO) of Atg5 in female microglia failed to obtain disease-associated microglia (DAM) gene signatures in familiar AD mouse model (5xFAD). Next, we analyzed the maintenance and neurogenesis of neural stem cells (NSCs) in the hippocampus and subventricular zone (SVZ) from 5xFAD mice with Atg5 cKO. Our data indicated that Atg5 cKO reduced the NSC number in hippocampus of female but not male 5xFAD mice. However, in the SVZ, Atg5 cKO only impaired NSCs in male 5xFAD mice. Interestingly, female 5xFAD;Fip200 cKO mice and 5xFAD;Atg14 cKO mice did not show NSC defects. These autophagy genes cKO 5xFAD mice exhibited a higher neurogenesis activity in their SVZ. Together, our data indicate a sex-specific role for microglial Atg5 in postnatal neurogenesis in AD mice.

A slowly progressive hereditary neurological disorder classified as degenerative encephalopathy (DE) occurs in Nova Scotia Duck Tolling Retrievers. The disease is characterized by frequent episodes of pronounced involuntary movements during sleep, cognitive impairment, anxiety, heightened sensitivity to sensory stimuli, and compulsive behaviors. The clinical signs are accompanied by the degeneration of several brain regions. A study was undertaken to identify the molecular genetic basis of this disorder.

Whole genome sequences (WGSs) from the DNA of affected and unaffected Nova Scotia Duck Tolling Retrievers were aligned to the Dog10K_Boxer_Tasha reference genome assembly and to the WGSs of 334 additional control dogs generated by this laboratory.

A missense C>T variant was identified in RB1CC1 exon 22 chromosome 29:4891014 that was uniquely homozygous in the affected dog. This variant predicts a p.G1503R change in the amino acid sequence of RB1CC1. Genotyping of 2950 Nova Scotia Duck Tolling Retrievers at the variant locus found complete concordance between the disease phenotype and RB1CC1 genotype.

RBCC1 is an essential component of a protein complex that mediates the initiation of autophagosome formation. Therefore, it appears likely that the disease results, at least in part, from impaired autophagy. Consistent with this possibility, brain neurons of an affected dog were found to contain abnormal lysosomal storage body-like inclusions. This disorder could serve as a valuable model to elucidate the mechanisms underlying human diseases associated with impaired autophagy. Identification of the disease-causing DNA sequence variant will enable owners of Nova Scotia Duck Tolling Retrievers to screen their dogs for the RB1CC1 risk variant.

Autophagy is a vital mechanism that eliminates large cytoplasmic components via lysosomal degradation to maintain cellular homeostasis. The role of autophagy in cancer treatment has been studied extensively. Autophagy primarily prevents tumour initiation by maintaining genomic stability and preventing cellular inflammation. However, autophagy also supports cancer cell survival and growth by providing essential nutrients for therapeutic resistance. Thus, autophagy has emerged as a promising strategy for overcoming resistance and enhancing anti-cancer therapy. Inhibiting autophagy significantly improves the sensitivity of lung, colorectal, breast, liver and prostate cancer cells to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). This review investigates the intricate interplay between autophagy modulation and TRAIL-based therapy, specifically focussing on comparing the efficacy of late-stage autophagy inhibition versus early-stage inhibition in overcoming cancer resistance. We expose the distinctive advantages of late-stage autophagy inhibition by exploring the mechanisms underlying autophagy's impact on TRAIL sensitivity. Current preclinical and clinical investigations are inspected, showing the potential of targeting late-stage autophagy for sensitizing resistant cancer cells to TRAIL-induced apoptosis. This review emphasizes the significance of optimizing autophagy modulation to enhance TRAIL-mediated therapy and overcome the challenge of treatment resistance in cancer. We offer insights and recommendations for guiding the development of potential therapeutic strategies aimed at overcoming the challenges posed by treatment-resistant cancers.

Cancer treatment has witnessed revolutionary advancements marked by the emergence of immunotherapy, specifically immune checkpoint blockade (ICB). However, the inherent low immunogenicity of tumor cells and the intricate immunosuppressive network within the tumor microenvironment (TME) pose significant challenges to the further development of immunotherapy. Nanotechnology has ushered in unprecedented opportunities and vast prospects for tumor immunotherapy. Nevertheless, traditional nano-formulations often rely on inducing apoptosis to kill cancer cells, which encounters the issue of immune silencing, hindering effective tumor immune activation. The non-apoptotic modes of regulated cell death (RCD), including pyroptosis, ferroptosis, autophagy, necroptosis, and cuproptosis, have gradually garnered attention. These non-apoptotic cell death pathways can induce effective immunogenic cell death (ICD), enhancing cancer immunotherapy. This review comprehensively explores advanced nano-formulation design strategies and their applications in enhancing cancer immunotherapy by promoting non-apoptotic RCD in recent years. It also discusses the potential advantages of these strategies in inducing tumor-specific non-apoptotic RCD. By deeply understanding the significance of non-apoptotic RCD in synergistic cancer immunotherapy, this article provides valuable insights for developing more advanced nano-delivery systems that can robustly induce highly immunogenic non-apoptotic modes, offering novel research and development avenues to address the clinical challenges encountered by immunotherapy represented by ICB.

Cancer is the second leading cause of death worldwide. >90 % of cancer-related deaths are due to metastasis, a process that depends on the ability of cancer cells to leave the primary tumor, migrate, and colonize different tissues. Inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays an essential role in maintaining the homeostasis of cancer cells and the sustained proliferation. Desmethylxestospongin B (dmXeB) is a specific inhibitor of the IP3R that selectively arrests cell proliferation and promotes cancer cell death at high concentrations. However, whether migration, invasion and metastasis can be affected by this drug is unknown. Here, by using the highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231, we demonstrate that a prolonged inhibition of IP3R-mediated Ca2+ signals with dmXeB significantly reduces cell migration and invasion in vitro and metastasis in vivo. We found that this phenomenon was independent of the bioenergetic control of IP3R over the mitochondria and AMPK activation. Furthermore, employing a tandem LC3-GFP-mcherry assay, we found that prolonged inhibition of IP3R with dmXeB leads to diminished autophagic flux. This reduction can be attributed to impaired lysosomal acidification, as evidenced by assessments using DQ-BSA and pHrodo. Since cell migration requires appropriate assembly and disassembly of focal adhesions, along with the internalization and recycling of integrins via autophagy, we explored the dependency of integrin recycling from autophagosomes, finding that IP3R inhibition with dmXeB impaired the recycling of β1-integrins, which accumulated within autophagosomes. Our findings reveal an unexpected effect of IP3R inhibition with dmXeB in cancer cells that could represent a novel therapeutic strategy for the treatment of cancer metastasis.

Breast cancer is a heterogeneous disease, with a subpopulation of tumor cells known as breast cancer stem cells (BCSCs) with self-renewal and differentiation abilities that play a critical role in tumor initiation, progression, and therapy resistance. The tumor microenvironment (TME) is a complex area where diverse cancer cells reside creating a highly interactive environment with secreted factors, and the extracellular matrix. Autophagy, a cellular self-digestion process, influences dynamic cellular processes in the tumor TME integrating diverse signals that regulate tumor development and heterogeneity. Autophagy acts as a double-edged sword in the breast TME, with both tumor-promoting and tumor-suppressing roles. Autophagy promotes breast tumorigenesis by regulating tumor cell survival, migration and invasion, metabolic reprogramming, and epithelial-mesenchymal transition (EMT). BCSCs harness autophagy to maintain stemness properties, evade immune surveillance, and resist therapeutic interventions. Conversely, excessive, or dysregulated autophagy may lead to BCSC differentiation or cell death, offering a potential avenue for therapeutic exploration. The molecular mechanisms that regulate autophagy in BCSCs including the mammalian target of rapamycin (mTOR), AMPK, and Beclin-1 signaling pathways may be potential targets for pharmacological intervention in breast cancer. This review provides a comprehensive overview of the relationship between autophagy and BCSCs, highlighting recent advancements in our understanding of their interplay. We also discuss the current state of autophagy-targeting agents and their preclinical and clinical development in BCSCs.

Resistance to androgen receptor (AR)-targeted therapies for prostate cancer (PCa) is characteristic of an aggressive subtype called castration-resistant prostate cancer (CRPC) and is often associated with tumor relapse. Both relapse and poor prognosis in patients with CRPC are associated with increased abundance of the E3 ubiquitin ligase SKP2. Therefore, we investigated the therapeutic potential of combined inhibition of AR and SKP2 for CRPC. We found that combined targeting of AR and SKP2 with small-molecule inhibitors decreased proliferation in two CRPC cell lines in culture and in xenografts in humanized mice. Furthermore, combined therapy in mice markedly decreased the growth of Pten/Trp53 double-knockout tumors, a particularly invasive model of CRPC, whereas disruption of either AR or SKP2 alone only modestly suppressed their growth. Mechanistically, the inhibition of SKP2 in CRPC cells induced autophagy-dependent apoptosis and promoted luminal-associated phenotypes, which promoted responsiveness to AR-targeted therapy. These effects were further enhanced by coinhibition of AR and were not induced by the AR inhibitor alone. Our findings indicate that targeting both AR and SKP2 signaling pathways is necessary to treat CRPC.

Cell death is a fundamental part of life for metazoans. To maintain the balance between cell proliferation and metabolism of human bodies, a certain number of cells need to be removed regularly. Hence, the mechanisms of cell death have been preserved during the evolution of multicellular organisms. Tumorigenesis is closely related with exceptional inhibition of cell death. Mutations or defects in cell death-related genes block the elimination of abnormal cells and enhance the resistance of malignant cells to chemotherapy. Therefore, the investigation of cell death mechanisms enables the development of drugs that directly induce tumor cell death. In the guidelines updated by the Cell Death Nomenclature Committee (NCCD) in 2018, cell death was classified into 12 types according to morphological, biochemical and functional classification, including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, PARP-1 parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence and mitotic catastrophe. The mechanistic relationships between epigenetic controls and cell death in cancer progression were previously unclear. In this review, we will summarize the mechanisms of cell death pathways and corresponding epigenetic regulations. Also, we will explore the extensive interactions between these pathways and discuss the mechanisms of cell death in epigenetics which bring benefits to tumor therapy.

Autophagy is an intracellular degradation process that sequesters cytoplasmic components in double-membrane vesicles known as autophagosomes, which are degraded upon fusion with lysosomes. This pathway maintains the integrity of proteins and organelles while providing energy and nutrients to cells, particularly under nutrient deprivation. Deregulation of autophagy can cause genomic instability, low protein quality, and DNA damage, all of which can contribute to cancer. Autophagy can also be overactivated in cancer cells to aid in cancer cell survival and drug resistance. Emerging evidence indicates that autophagy has functions beyond cargo degradation, including roles in tumor immunity and cancer stem cell survival. Additionally, autophagy can also influence the tumor microenvironment. This feature warrants further investigation of the role of autophagy in cancer, in which autophagy manipulation can improve cancer therapies, including cancer immunotherapy. This review discusses recent findings on the regulation of autophagy and its role in cancer therapy and drug resistance.

Lysosomes are essential intracellular catabolic organelles that contain digestive enzymes involved in the degradation and recycle of damaged proteins, organelles, etc. Thus, they play an important role in various biological processes, including autophagy regulation, ion homeostasis, cell death, cell senescence. A myriad of studies has shown that the dysfunction of lysosome is implicated in human aging and various age-related diseases, including cancer. However, what is noteworthy is that the modulation of lysosome-based signaling and degradation has both the cancer-suppressive and cancer-promotive functions in diverse cancers depending on stage, biology, or tumor microenvironment. This dual role limits their application as targets in cancer therapy. In this review, we provide an overview of lysosome and autophagy-lysosomal pathway and outline their critical roles in many cellular processes, including cell death. We highlight the different functions of autophagy-lysosomal pathway in cancer development and progression, underscoring its potential as a target for effective cancer therapies.

Type I interferons (IFN-I) are potent alarm factors that initiate cancer cell elimination within tumors by the immune system. This critical immune response is often suppressed in aggressive tumors, thereby facilitating cancer immune escape and unfavorable patient outcome. The mechanisms underpinning IFN-I suppression in tumors are incompletely understood. Arginase-1 (ARG1)-expressing immune cells that infiltrate tumors can restrict arginine availability by ARG1-mediated arginine degradation. We hypothesized that arginine restriction suppresses the IFN-I response in tumors.

Comprehensive, unbiased open approach omics analyses, various in vitro techniques, including microscopy, qPCR, immunoblotting, knock-down experiments, and flow cytometry were employed, as well as ex vivo analysis of tumor tissue from mice. Several functional bioassays were utilized to assess metabolic functions and autophagy activity in cancer cells.

Arginine restriction potently induced expression of selective autophagy receptors, enhanced bulk and selective autophagy and strongly suppressed the IFN-I response in cancer cells in an autophagy-dependent manner.

Our study proposes a mechanism for how tumor-infiltrating immune cells can promote cancer immune escape by dampening the IFN-I response. We suggest ARG1 and autophagy as putative therapeutic targets to activate the IFN-I response in tumors.

Adiponectin, a unique adipose-derived factor, is significantly downregulated in obesity, making it a crucial target for tumor-related metabolic research. AdipoRon is a novel adiponectin receptor agonist with the advantages of a small molecular weight, high stability and a long half-life. By screening the cervical adipose tissue of papillary thyroid carcinoma (PTC) patients with adipokine antibody array, we found that adiponectin was a potential correlation factor between obesity and PTC progression. AdipoRon has oral activity and is easily absorbed and delivered to target tissues. The effects of AdipoRon on thyroid cancer have not been reported. In this study, we identified adiponectin receptor 1 (AdipoR1) and AdipoR2 on the surface of thyroid cancer cell lines. AdipoRon inhibited the proliferation and migration of thyroid cancer cells, limited energy metabolism in thyroid cancer cells, promoted differentiation of thyroid cancer cells, and induced autophagy and apoptosis. Mechanistic studies revealed that AdipoRon inhibited p-mTOR Ser2448 and p-p70S6K Thr389, and activated ULK1 and p-ULK1. ULK1 knockdown suppressed the effect of AdipoRon on LC3BII/I protein and lysosomes. AdipoR2 knockdown reduced AdipoRon-induced autophagy in thyroid cancer cells. This study is the first to demonstrate the role of AdipoRon in PTC. Our findings illustrate a previously unknown function and mechanism of the AdipoRon-AdipoR2-ULK/p-ULK1 axis in PTC and lay the foundation for clinical translation of AdipoRon to PTC. Targeting the AdipoRon-AdipoR2-ULK/p-ULK1 axis may represent a new therapeutic strategy for PTC.

An immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti-programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine 10 (CXCL10) chemokines. The purpose of this study was to investigate the signaling mechanism leading to the VPS34-dependent chemokine increase. NanoString gene expression analysis was applied to tumors from mice treated with the VPS34 inhibitor SB02024 to identify key pathways involved in the anti-tumor response. We showed that VPS34 inhibitors increased the secretion of T-cell-recruitment chemokines in a cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING)-dependent manner in cancer cells. Both pharmacological and small interfering RNA (siRNA)-mediated VPS34 inhibition increased cGAS/STING-mediated expression and secretion of CCL5 and CXCL10. The combination of VPS34 inhibitor and STING agonist further induced cytokine release in both human and murine cancer cells as well as monocytic or dendritic innate immune cells. Finally, the VPS34 inhibitor SB02024 sensitized B16-F10 tumor-bearing mice to STING agonist treatment and significantly improved mice survival. These results show that VPS34 inhibition augments the cGAS/STING pathway, leading to greater tumor control through immune-mediated mechanisms. We propose that pharmacological VPS34 inhibition may synergize with emerging therapies targeting the cGAS/STING pathway.

There has been interest in the connection between cardiovascular diseases and osteoporosis, both of which share hyperlipidemia as a common pathological basis. Osteoporosis is a progressive metabolic bone disease characterized by reduced bone mass, deteriorated bone microstructure, increased bone fragility and heightened risk of bone fractures. Dysfunction of osteoblastic cells, vital for bone formation, is induced by excessive internalization of lipids under hyperlipidemic conditions, forming the crux of hyperlipidemia-associated osteoporosis. Autophagy, a process fundamental to cell self-regulation, serves a critical role in osteoblastic cell function and bone formation. When activated by lipids, lipophagy inhibits osteoblastic cell differentiation in response to elevated lipid concentrations, resulting in reduced bone mass and osteoporosis. However, an in-depth understanding of the precise roles and mechanisms of lipophagy in the regulation of osteoblastic cell function is required. Study of the molecular mechanisms governing osteoblastic cell response to excessive lipids can result in a clearer understanding of osteoporosis; therefore, potential strategies for preventing hyperlipidemia-induced osteoporosis can be developed. The present review discusses recent progress in elucidating the molecular mechanisms of lipophagy in the regulation of osteoblastic cell function, offering insights into hyperlipidemia-induced osteoporosis.

The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.

Metastasis, the spread, and growth of malignant cells at secondary sites within a patient's body, accounts for over 90% of cancer-related mortality. Breast cancer is the most common tumor type diagnosed and the leading cause of cancer lethality in women in the United States. It is estimated that 10-16% breast cancer patients will have brain metastasis. Current therapies to treat patients with breast cancer brain metastasis (BCBM) remain palliative. This is largely due to our limited understanding of the fundamental molecular and cellular mechanisms through which BCBM progresses, which represents a critical barrier for the development of efficient therapies for affected breast cancer patients.

Previous research in BCBM relied on co-culture assays of tumor cells with rodent neural cells or rodent brain slice ex vivo. Given the need to overcome the obstacle for human-relevant host to study cell-cell communication in BCBM, we generated human embryonic stem cell-derived cerebral organoids to co-culture with human breast cancer cell lines. We used MDA-MB-231 and its brain metastatic derivate MDA-MB-231 Br-EGFP, other cell lines of MCF-7, HCC-1806, and SUM159PT. We leveraged this novel 3D co-culture platform to investigate the crosstalk of human breast cancer cells with neural cells in cerebral organoid.

We found that MDA-MB-231 and SUM159PT breast cancer cells formed tumor colonies in human cerebral organoids. Moreover, MDA-MB-231 Br-EGFP cells showed increased capacity to invade and expand in human cerebral organoids.

Our co-culture model has demonstrated a remarkable capacity to discern the brain metastatic ability of human breast cancer cells in cerebral organoids. The generation of BCBM-like structures in organoid will facilitate the study of human tumor microenvironment in culture.

Macroautophagy (autophagy hereafter) is an intracellular nutrient scavenging pathway induced by starvation and other stressors whereby cellular components such as organelles are captured in double-membrane vesicles (autophagosomes), whereupon their contents are degraded through fusion with lysosomes. Two main purposes of autophagy are to recycle the intracellular breakdown products to sustain metabolism and survival during starvation and to eliminate damaged or excess cellular components to suppress inflammation and maintain homeostasis. In contrast to most normal cells and tissues in the fed state, tumor cells up-regulate autophagy to promote their growth, survival, and malignancy. This tumor-cell-autonomous autophagy supports elevated metabolic demand and suppresses tumoricidal activation of the innate and adaptive immune responses. Tumor-cell-nonautonomous (e.g., host) autophagy also supports tumor growth by maintaining essential tumor nutrients in the circulation and tumor microenvironment and by suppressing an antitumor immune response. In the setting of cancer therapy, autophagy is a resistance mechanism to chemotherapy, targeted therapy, and immunotherapy. Thus, tumor and host autophagy are protumorigenic and autophagy inhibition is being examined as a novel therapeutic approach to treat cancer.

Autophagy, a conserved cellular degradation process, is crucial for various cellular processes such as immune responses, inflammation, metabolic and oxidative stress adaptation, cell proliferation, development, and tissue repair and remodeling. Dysregulation of autophagy is suspected in numerous diseases, including cancer, neurodegenerative diseases, digestive disorders, metabolic syndromes, and infectious and inflammatory diseases. If autophagy is disrupted, for example, this can have serious consequences and lead to chronic inflammation and tissue damage, as occurs in diseases such as Chron's disease and ulcerative colitis. On the other hand, the influence of autophagy on the development and progression of cancer is not clear. Autophagy can both suppress and promote the progression and metastasis of cancer at various stages. From inflammatory bowel diseases to gastrointestinal cancer, researchers are discovering the intricate role of autophagy in maintaining gut health and its potential as a therapeutic target. Researchers should carefully consider the nature and progression of diseases such as cancer when trying to determine whether inhibiting or stimulating autophagy is likely to be beneficial. Multidisciplinary approaches that combine cutting-edge research with clinical expertise are key to unlocking the full therapeutic potential of autophagy in digestive diseases.

Cancer is the result of genetic abnormalities that cause normal cells to grow into neoplastic cells. Cancer is characterized by several distinct features, such as uncontrolled cell growth, extensive spreading to other parts of the body, and the ability to resist treatment. The scientists have stressed the development of nanostructures as novel therapeutic options in suppressing cancer, in response to the emergence of resistance to standard medicines. One of the specific mechanisms with dysregulation during cancer is autophagy. Nanomaterials have the ability to specifically carry medications and genes, and they can also enhance the responsiveness of tumor cells to standard therapy while promoting drug sensitivity. The primary mechanism in this process relies on autophagosomes and their fusion with lysosomes to break down the components of the cytoplasm. While autophagy was initially described as a form of cellular demise, it has been demonstrated to play a crucial role in controlling metastasis, proliferation, and treatment resistance in human malignancies. The pharmacokinetic profile of autophagy modulators is poor, despite their development for use in cancer therapy. Consequently, nanoparticles have been developed for the purpose of delivering medications and autophagy modulators selectively and specifically to the cancer process. Furthermore, several categories of nanoparticles have demonstrated the ability to regulate autophagy, which plays a crucial role in defining the biological characteristics and response to therapy of tumor cells.

The considerable death rates and lack of symptoms in early stages of gastric cancer (GC) make it a major health problem worldwide. One of the most prominent risk factors is infection with Helicobacter pylori. Many biological processes, including those linked with cell death, are disrupted in GC. The cellular "self-digestion" mechanism necessary for regular balance maintenance, autophagy, is at the center of this disturbance. Misregulation of autophagy, however, plays a role in the development of GC. In this review, we will examine how autophagy interacts with other cell death processes, such as apoptosis and ferroptosis, and how it affects the progression of GC. In addition to wonderful its role in the epithelial-mesenchymal transition, it is engaged in GC metastasis. The role of autophagy in GC in promoting drug resistance stands out. There is growing interest in modulating autophagy for GC treatment, with research focusing on natural compounds, small-molecule inhibitors, and nanoparticles. These approaches could lead to breakthroughs in GC therapy, offering new hope in the fight against this challenging disease.

Macroautophagy/autophagy is the intracellular degradation process of cytoplasmic content and damaged organelles. Autophagy is strongly associated with the progression of Alzheimer disease (AD). Microglia are brain-resident macrophages, and recent studies indicate that autophagy in microglia protects neurons from neurodegeneration. Postnatal neurogenesis, the generation of new neurons from adult neural stem cells (NSCs), is impaired in AD patients as well as in AD animal models. However, the extent to which microglial autophagy influences adult NSCs and neurogenesis in AD animal models has not been studied. Here, we showed that conditional knock out (cKO) of Atg5 (autophagy related 5) in microglia inhibited postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus, but not in the subventricular zone (SVZ) of a 5×FAD mouse model. Interestingly, the protection of neurogenesis by Atg5 in microglia was only observed in female AD mice. To confirm the roles of autophagy in microglia for postnatal hippocampal neurogenesis, we generated additional cKO mice to delete autophagy essential genes Rb1cc1 or Atg14 in microglia. However, these rb1cc1 cKO and atg14 cKO mice did not exhibit neurogenesis defects in the context of a female AD mouse model. Last, we used the CSF1R antagonist to deplete ATG5-deficient microglia and this intervention restored neurogenesis in the hippocampus of 5×FAD mice. These results indicate that microglial ATG5 is essential to maintain postnatal hippocampal neurogenesis in a mouse model of AD. Our findings further support the notion that ATG5 in microglia supports NSC health and may prevent neurodegeneration.Abbreviations: 5×FAD: familial Alzheimer disease; Aβ: β-amyloid; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; ATG: autophagy related; BrdU: 5-bromo-2'-deoxyuridine; CA: Cornu Ammonis; cKO: conditional knock out; CSF1R: colony stimulating factor 1 receptor; Ctrl: control; DCX: doublecortin; DG: dentate gyrus; GFAP: glial fibrillary acidic protein; GZ: granular zone; H&E: hematoxylin and eosin; IF: immunofluorescence; LD: lipid droplet; LDAM: lipid droplets accumulated microglia; LPS: lipopolysaccharides; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; NSCs: neural stem cells; RB1CC1: RB1-inducible coiled-coil 1; SOX2: SRY (sex determining region Y)-box 2; SGZ: subgranular zone; SVZ: subventricular zone; WT: wild type.

Most breast cancers do not respond to immune checkpoint inhibitors and there is an urgent need to identify novel sensitization strategies. Herein, we uncovered that activation of the TBK-IFN pathway that is mediated by the TBK1 adapter protein AZI2 is a potent strategy for this purpose. Our initial observations showed that RB1CC1 depletion leads to accumulation of AZI2, in puncta along with selective macroautophagy/autophagy cargo receptors, which are both required for TBK1 activation. Specifically, disrupting the selective autophagy function of RB1CC1 was sufficient to sustain AZI2 puncta accumulation and TBK1 activation. AZI2 then mediates downstream activation of DDX3X, increasing its interaction with IRF3 for transcription of pro-inflammatory chemokines. Consequently, we performed a screen to identify inhibitors that can induce the AZI2-TBK1 pathway, and this revealed Lys05 as a pharmacological agent that induced pro-inflammatory chemokine expression and CD8+ T cell infiltration into tumors. Overall, we have identified a distinct AZI2-TBK1-IFN signaling pathway that is responsive to selective autophagy blockade and can be activated to make breast cancers more immunogenic.Abbreviations: AZI2/NAP1: 5-azacytidine induced 2; CALCOCO2: calcium binding and coiled-coil domain 2; DDX3X: DEAD-box helicase 3 X-linked; FCCP: carbonyl cyanide p-triflouromethoxyphenylhydrazone; a protonophore that depolarizes the mitochondrial inner membrane; ICI: immune checkpoint inhibitor; IFN: interferon; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1.

Autophagy is a conserved cellular process, and its dysfunction is implicated in cancer and other diseases. Here, we employ an in vivo CRISPR screen targeting genes implicated in the regulation of autophagy to identify the Nsfl1c gene encoding p47 as a suppressor of human epidermal growth factor receptor 2 (HER2)+ breast cancer metastasis. p47 ablation specifically increases metastasis without promoting primary mammary tumor growth. Analysis of human breast cancer patient databases and tissue samples indicates a correlation of lower p47 expression levels with metastasis and decreased survival. Mechanistic studies show that p47 functions in the repair of lysosomal damage for autophagy flux and in the endosomal trafficking of nuclear factor κB essential modulator for lysosomal degradation to promote metastasis. Our results demonstrate a role and mechanisms of p47 in the regulation of breast cancer metastasis. They highlight the potential to exploit p47 as a suppressor of metastasis through multiple pathways in HER2+ breast cancer cells.

Autophagy is a form of programmed cell degradation that enables the maintenance of homeostasis in response to extracellular stress stimuli. Autophagy is primarily activated by starvation and mediates the degradation, removal, or recycling of cell cytoplasm, organelles, and intracellular components in eukaryotic cells. Autophagy is also involved in the pathogenesis of human diseases, including several cancers. Human uveal melanoma (UM) is the primary intraocular malignancy in adults and has an extremely poor prognosis; at present there are no effective therapies. Several studies have suggested that autophagy is important in UM. By understanding the mechanisms of activation of autophagy in UM it may be possible to develop biomarkers to provide more definitive disease prognoses and to identify potential drug targets for the development of new therapeutic strategies. This article reviews the current information regarding autophagy in UM that could facilitate biomarker and drug development.

Recently, biomembrane nanostructures, such as liposomes, cell membrane-coated nanostructures, and exosomes, have demonstrated promising anticancer therapeutic effects. These nanostructures possess remarkable biocompatibility, multifunctionality, and low toxicity. However, their therapeutic efficacy is impeded by chemoresistance and radiotherapy resistance, which are closely associated with autophagy. Modulating autophagy could enhance the therapeutic sensitivity and effectiveness of these biomembrane nanostructures by influencing the immune system and the cancer microenvironment. For instance, autophagy can regulate the immunogenic cell death of cancer cells, antigen presentation of dendritic cells, and macrophage polarization, thereby activating the inflammatory response in the cancer microenvironment. Furthermore, combining autophagy-regulating drugs or genes with biomembrane nanostructures can exploit the targeting and long-term circulation properties of these nanostructures, leading to increased drug accumulation in cancer cells. This review explores the role of autophagy in carcinogenesis, cancer progression, metastasis, cancer immune responses, and resistance to treatment. Additionally, it highlights recent research advancements in the synergistic anticancer effects achieved through autophagy regulation by biomembrane nanostructures. The review also discusses the prospects and challenges associated with the future clinical translation of these innovative treatment strategies. In summary, these findings provide valuable insights into autophagy, autophagy-modulating biomembrane-based nanostructures, and the underlying molecular mechanisms, thereby facilitating the development of promising cancer therapeutics.

Epidemiological as well as experimental studies have established that the pineal hormone melatonin has inhibitory effects on different types of cancers. Several mechanisms have been proposed for the anticancer activities of melatonin, but the fundamental molecular pathways still require clarity. We developed a mouse model of breast cancer using Ehrlich's ascites carcinoma (injected in the 4th mammary fat pad of female Swiss albino mice) and investigated the possibility of targeting the autophagy-inflammation-EMT colloquy to restrict breast tumor progression using melatonin as intervention. Contrary to its conventional antioxidant role, melatonin was shown to augment intracellular ROS and initiate ROS-dependent apoptosis in our system, by modulating the p53/JNK & NF-κB/pJNK expressions/interactions. Melatonin-induced ROS promoted SIRT1 activity. Interplay between SIRT1 and NF-κB/p65 is known to play a pivotal role in regulating the crosstalk between autophagy and inflammation. Persistent inflammation in the tumor microenvironment and subsequent activation of the IL-6/STAT3/NF-κB feedback loop promoted EMT and suppression of autophagy through activation of PI3K/Akt/mTOR signaling pathway. Melatonin disrupted NF-κB/SIRT1 interactions blocking IL-6/STAT3/NF-κB pathway. This led to reversal of pro-inflammatory bias in the breast tumor microenvironment and augmented autophagic responses. The interactions between p62/Twist1, NF-κB/Beclin1 and NF-κB/Slug were altered by melatonin to strike a balance between autophagy, inflammation and EMT, leading to tumor regression. This study provides critical insights into how melatonin could be utilized in treating breast cancer via inhibition of the PI3K/Akt/mTOR signaling and differential modulation of SIRT1 and NF-κB proteins, leading to the establishment of apoptotic and autophagic fates in breast cancer cells.

Autophagy is a significant catabolic procedure that increases in stressful conditions. This mechanism is mostly triggered after damage to the organelles, the presence of unnatural proteins, and nutrient recycling in reaction to these stresses. One of the key points in this article is that cleaning and preserving damaged organelles and accumulated molecules through autophagy in normal cells helps prevent cancer. Since dysfunction of autophagy is associated with various diseases, including cancer, it has a dual function in tumor suppression and expansion. It has newly become clear that the regulation of autophagy can be used for the treatment of breast cancer, which has a promising effect of increasing the efficiency of anticancer treatment in a tissue- and cell-type-specific manner by affecting the fundamental molecular mechanisms. Regulation of autophagy and its function in tumorigenesis is a vital part of modern anticancer techniques. This study discusses the current advances related to the mechanisms that describe essential modulators of autophagy involved in the metastasis of cancers and the development of new breast cancer treatments.

CD133 is widely used as a marker to isolate tumor-initiating cells in many types of cancers. The structure of N-glycan on CD133 is altered during the differentiation of tumor-initiating cells. However, the relationship between CD133 N-glycosylation and stem cell characteristics remains elusive. Here, we found that the level of α-1,2-mannosylated CD133 was associated with the level of stemness genes in intrahepatic cholangiocarcinoma (iCCA) tissues. α-1,2-mannosylated CD133+ cells possessed the characteristics of tumor-initiating cells. The loss of the Golgi α-mannosidase I coding gene MAN1C1 resulted in the formation of α-1,2-mannosylated CD133 in iCCA-initiating cells. Mechanistically, α-1,2-mannosylation promoted the cytoplasmic distribution of CD133 and enhanced the interaction between CD133 and the autophagy gene FIP200, subsequently promoting the tumorigenesis of α-1,2-mannosylated CD133+ cells. Analysis of iCCA samples showed that the level of cytoplasmic CD133 was associated with poor iCCA prognosis. Collectively, α-1,2-mannosylated CD133 is a functional marker of iCCA-initiating cells.

Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer.

Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.

Sonodynamic therapy (SDT) is a new non-invasive treatment method proposed based on photodynamic therapy (PDT). It has advantages such as high precision, strong tissue penetration, minimal side effects, and good patient compliance. With the maturation of nanomedicine, the application of nanosonosensitizers has further propelled the development of SDT. In recent years, people have developed many new types of sonosensitizers and explored the mechanisms of SDT. Among them, the studies about the relationship between autophagy and SDT have attracted increasing attention. After the SDT, cells usually undergo autophagy as a self-protective mechanism to resist external stimuli and reduce cell damage, which is beneficial for the treatment of atherosclerosis (AS), diabetes, and myocardial infarction but counterproductive in cancer treatment. However, under certain treatment conditions, excessive upregulation of autophagy can also promote cell death, which is beneficial for cancer treatment. This article reviews the latest research progress on the relationship between SDT and autophagy in cancers, AS, diabetes, and myocardial infarction. We also discuss and propose the challenges and prospects in enhancing SDT efficacy by regulating autophagy, with the hope of promoting the development of this promising therapeutic approach.

Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular stresses. Mitophagy is a type of autophagy that is involved in the intricate removal of dysfunctional mitochondria during conditions of metabolic stress. In this review, we describe the multifaceted roles of autophagy and mitophagy in normal physiology and the field of cancer biology. Autophagy and mitophagy exhibit dual context-dependent roles in cancer development, acting as tumor suppressors and promoters. We also discuss the important role of autophagy and mitophagy within the cancer microenvironment and how autophagy and mitophagy influence tumor host-cell interactions to overcome metabolic deficiencies and sustain the activity of cancer-associated fibroblasts (CAFs) in a stromal environment. Finally, we explore the dynamic interplay between autophagy and the immune response in tumors, indicating their potential as immunomodulatory targets in cancer therapy. As the field of autophagy and mitophagy continues to evolve, this comprehensive review provides insights into their important roles in cancer and cancer microenvironment.

Autophagy is a well-conserved intracellular degradation pathway. Besides its physiological role in normal cells, autophagy is activated in various cancer types and protects cancer cells from stresses such as nutrient deprivation, therapeutic insults, and antitumor immunity. Autophagy in cancer cells as well as normal cells in the host supports tumor metabolism, allowing for tumor growth under a nutrient-limited tumor microenvironment. Autophagy also protects cancer cells from treatments such as radiation therapy, cytotoxic chemotherapy, and targeted therapy. Though the roles of autophagy in antitumor immunity are complex and highly context-dependent, accumulating evidence now supports the role of autophagy in mediating immunotherapy resistance. Based on these preclinical findings, multiple clinical trials are currently ongoing to test the therapeutic efficacy of autophagy inhibition in cancer. Here, we review recent findings on the tumor-promoting roles of autophagy in cancer and discuss advances in therapeutic approaches that target autophagy in cancer.

Modulation of autophagy as an anticancer strategy has been widely studied and evaluated in several cell models. However, little attention has been paid to the metabolic changes that occur in a cancer cell when autophagy is inhibited or induced. In this review, we describe how the expression and regulation of various autophagy-related (ATGs) genes and proteins are associated with cancer progression and cancer plasticity. We present a comprehensive review of how deregulation of ATGs affects cancer cell metabolism, where inhibition of autophagy is mainly reflected in the enhancement of the Warburg effect. The importance of metabolic changes, which largely depend on the cancer type and form part of a cancer cell's escape strategy after autophagy modulation, is emphasized. Consequently, pharmacological strategies based on a dual inhibition of metabolic and autophagy pathways emerged and are reviewed critically here.

Gastrointestinal cancer has always been one of the most urgent problems to be solved, and it has become a major global health issue. Microorganisms in the gastrointestinal tract regulate normal physiological and pathological processes. Accumulating evidence reveals the role of the imbalance in the microbial community during tumorigenesis. Autophagy is an important intracellular homeostatic process, where defective proteins and organelles are degraded and recycled under stress. Autophagy plays a dual role in tumors as both tumor suppressor and tumor promoter. Many studies have shown that autophagy plays an important role in response to microbial infection. Here, we provide an overview on the regulation of the autophagy signaling pathway by microorganisms in gastrointestinal cancer.

Autophagy is well-known as an internal catabolic process that is evolutionarily conserved and performs the key biological function in maintaining cellular homeostasis. It is tightly controlled by several autophagy-related (ATG) proteins, which are closely associated with many types of human cancers. However, what has remained controversial is the janus roles of autophagy in cancer progression. Interestingly, the biological function of long non-coding RNAs (lncRNAs) in autophagy has been gradually understood in different types of human cancers. More recently, numerous studies have demonstrated that several lncRNAs may regulate some ATG proteins and autophagy-related signaling pathways to either activate or inhibit the autophagic process in cancer. Thus, in this review, we summarize the latest advance in the knowledge of the complicated relationships between lncRNAs and autophagy in cancer. Also, the in-depth dissection of the lncRNAs-autophagy-cancers axis involved in this review would shed new light on discovery of more potential cancer biomarkers and therapeutic targets in the future.

Autophagy is an intracellular process that plays a key role in the cellular homeostasis. Recently, it has been described as a potential therapeutic target in oncology, whether by activating or inhibiting its different cascades. Autophagy inhibitors interact with different molecular processes of the hallmarks of cancer.

Multiple proteins of the autophagy cascade could be aimed by specific inhibitors in many tumors, notably bladder cancer. In fact, bladder cancer has been increasing in prevalence over the last decade, and resistance to conventional treatment has been extensively reported in the literature. Autophagy inhibitors in bladder cancer have been described in preclinical studies to increase the sensitivity of the tumor to chemotherapy and radiotherapy. This paper is a review of the literature, which selected randomized trials, cohort studies, and case-control studies documenting the relationship between autophagy inhibitors and bladder cancer treatment.

Autophagy is a promising pathway for cancer cell targeting that opens the horizons for a potential new therapeutic area in particular the multidisciplinary management of bladder cancer.

Head and neck squamous cell carcinoma (HNSCC) is a type of cancer that arises from the epithelium lining of the oral cavity, hypopharynx, oropharynx, and larynx. Despite the advancement of current treatments, including surgery, chemotherapy, and radiotherapy, the overall survival rate of patients afflicted with HNSCC remains poor. The reasons for these poor outcomes are due to late diagnoses and patient-acquired resistance to treatment. Natural products have been extensively explored as a safer and more acceptable alternative therapy to the current treatments, with numerous studies displaying their potential against HNSCC. This review highlights preclinical studies in the past 5 years involving natural products against HNSCC and explores the signaling pathways altered by these products. This review also addresses challenges and future directions of natural products as chemotherapeutic and chemoprevention agents against HNSCC.

Despite chimeric antigen receptor (CAR) T cell therapy's extraordinary success in subsets of B-cell lymphoma and leukemia, various barriers restrict its application in solid tumors. This has prompted investigating new approaches for producing CAR T cells with superior therapeutic potential. Emerging insights into the barriers to CAR T cell clinical success indicate that autophagy shapes the immune response via reprogramming cellular metabolism and vice versa. Autophagy, a self-cannibalization process that includes destroying and recycling intracellular components in the lysosome, influences T cell biology, including development, survival, memory formation, and cellular metabolism. In this review, we will emphasize the critical role of autophagy in regulating and rewiring metabolic circuits in CAR T cells, as well as how the metabolic status of CAR T cells and the tumor microenvironment (TME) alter autophagy regulation in CAR T cells to restore functional competence in CAR Ts traversing solid TMEs.