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Over the past decade, artificial intelligence (AI) has contributed substantially to the resolution of various medical problems, including cancer. Deep learning (DL), a subfield of AI, is characterized by its ability to perform automated feature extraction and has great power in the assimilation and evaluation of large amounts of complicated data. On the basis of a large quantity of medical data and novel computational technologies, AI, especially DL, has been applied in various aspects of oncology research and has the potential to enhance cancer diagnosis and treatment. These applications range from early cancer detection, diagnosis, classification and grading, molecular characterization of tumors, prediction of patient outcomes and treatment responses, personalized treatment, automatic radiotherapy workflows, novel anti‐cancer drug discovery, and clinical trials. In this review, we introduced the general principle of AI, summarized major areas of its application for cancer diagnosis and treatment, and discussed its future directions and remaining challenges. As the adoption of AI in clinical use is increasing, we anticipate the arrival of AI‐powered cancer care. This review introduced the general principle of AI, summarize major areas of its application for cancer diagnosis, treatment, and precision medicine and discuss its future directions and remaining challenges.

Pyroptosis is a form of regulated cell death mediated by gasdermin family members, among which the function of GSDMC has not been clearly described. Herein, we demonstrate that the metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of GSDMC. Treatment with DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels, which leads to oxidation of the plasma membrane-localized death receptor DR6. Oxidation of DR6 triggers its endocytosis, and then recruits both pro-caspase-8 and GSDMC to a DR6 receptosome through protein-protein interactions. The DR6 receptosome herein provides a platform for the cleavage of GSDMC by active caspase-8, thereby leading to pyroptosis. Moreover, this α-KG-induced pyroptosis could inhibit tumor growth and metastasis in mouse models. Interestingly, the efficiency of α-KG in inducing pyroptosis relies on an acidic environment in which α-KG is reduced by MDH1 and converted to L-2HG that further boosts ROS levels. Treatment with lactic acid, the end product of glycolysis, builds an improved acidic environment to facilitate more production of L-2HG, which makes the originally pyroptosis-resistant cancer cells more susceptible to α-KG-induced pyroptosis. This study not only illustrates a pyroptotic pathway linked with metabolites but also identifies an unreported principal axis extending from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in tumor therapy.

Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N -acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME T6E or GSDME T6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.

The cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) pathway is intimately associated with antitumoral immunity; however, the direct involvement of this pathway in tumor cell demise remains elusive. Here, we identified a compound, dodecyl 6-hydroxy-2-naphthoate (DHN), that induces pyroptosis in melanoma cells by activating noncanonical cGAS/STING signaling. DHN targets mitochondrial protein cyclophilin D (CypD) to induce the release of mitochondrial DNA, leading to cGAS activation and cyclic GMP-AMP (cGAMP) generation. Meanwhile, DHN-caused intracellular acidification induces protein kinase R-like endoplasmic reticulum kinase (PERK) activation, which promotes STING phosphorylation and polymerization in the presence of cGAMP, thereby facilitating the aggregation of STING in the ER, which serves as a platform to recruit Fas-associated via death domain (FADD) and caspase-8, leading to caspase-8 activation and subsequent gasdermin E cleavage, which ultimately results in pyroptosis of tumor cells and tumor regression in mouse models. The occurrence of this noncanonical cGAS/STING pathway-associated pyroptosis is also observed when both cGAS is activated and intracellular pH declines. Collectively, our findings reveal a pathway that links noncanonical cGAS/STING signaling to gasdermin E-mediated pyroptosis, thereby offering valuable insights for tumor therapy.

Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation. Gluconeogenesis is downregulated in hepatocellular carcinoma. Here, the authors show that nuclear receptor Nur77 acts as a tumour suppressor sustaining gluconeogenesis by enhancing phosphoenolpyruvate carboxykinase (PEPCK1) stability via regulating its interaction with the SUMO-conjugating enzyme Ubc9.

The orphan nuclear receptor Nur77 blocks inflammation through inhibition of p65 DNA binding and is suppressed by p38α-mediated phosphorylation. A small-molecule compound, PDNPA, disrupts p38α-Nur77 interactions and alleviates mouse models of sepsis. Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n -pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

Protein kinase AKT plays a broad role in promoting energy production in nutrient-rich environments. However, its roles under metabolic stress remain elusive. Herein, we demonstrate a dual mechanism for AKT activation during glucose deprivation. On one hand, glucose deprivation leads to increased levels of ADP and NADP + , which directly bind to spleen tyrosine kinase (SYK) and induce a conformational alteration of SYK, resulting in self-activation. The activated SYK further triggers PI3K-dependent activation of AKT. On the other hand, elevated ROS upon glucose deprivation promotes oxidative dimerization of PDK1, thereby facilitating the recognition and activation of AKT. In melanoma cells, AKT plays a critical role in elevating ROS levels and inducing cell death during glucose deprivation. Overall, this study not only establishes a novel connection between energy insufficiency and AKT activation via a dual mechanism but also provides insights into the role of AKT in sensitizing cells to metabolic stress.

TR3 is an orphan nuclear receptor with roles in apoptosis. A TR3-binding compound induces mitochondrial translocation of TR3 and autophagy via the Nix–Toms–ANT1/VDAC1 pathway, providing a mechanism for cell death in melanoma cells that are resistant to spontaneous and drug-induced apoptosis. Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1–VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

Background Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated efficacy in nasopharyngeal carcinoma (NPC). Thyroid dysfunction is among the most common immune-related adverse events. This study aimed to explore the clinical pattern of thyroid dysfunction and its relationship with survival marker in nonmetastatic NPC after immunotherapy. Methods From January 1, 2019, to December 31, 2021, 165 pairs of nonmetastatic NPC patients (165 with and 165 without anti-PD-1 immunotherapy) matched by the propensity score matching method were included in this study. Thyroid function was assessed retrospectively before the first treatment and during each immunotherapy cycle. Results The spectrum of thyroid dysfunction was different between the immunotherapy and control groups ( P < 0.001). Compared with the control group, patients in the immunotherapy group developed more hypothyroidism (14.545% vs. 7.273%), less hyperthyroidism (10.909% vs. 23.636%), and a distinct pattern, biphasic thyroid dysfunction (3.030% vs. 0%). Immunotherapy also accelerates the onset of hypothyroidism, which was earlier with a median onset time difference of 32 days ( P < 0.001). Patients who acquired thyroid dysfunction during immunotherapy had better complete biological response to treatment (OR, 10.980; P = 0.042). Conclusions For nonmetastatic NPC, thyroid dysfunction was associated with better response to treatment in immunotherapy but not in routine treatment. Thyroid function could be used as a predictor for survival and should be under regular and intensive surveillance in clinical practice of anti-PD-1 immunotherapy for nonmetastatic NPC.