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Abstract Regulatory T cells (Tregs) are essential to the negative regulation of the immune system, as they avoid excessive inflammation and mediate tumor development. The abundance of Tregs in tumor tissues suggests that Tregs may be eliminated or functionally inhibited to stimulate antitumor immunity. However, immunotherapy targeting Tregs has been severely hampered by autoimmune diseases due to the systemic elimination of Tregs. Recently, emerging studies have shown that metabolic regulation can specifically target tumor-infiltrating immune cells, and lipid accumulation in TME is associated with immunosuppression. Nevertheless, how Tregs actively regulate metabolic reprogramming to outcompete effector T cells (Teffs), and how lipid metabolic reprogramming contributes to the immunomodulatory capacity of Tregs have not been fully discussed. This review will discuss the physiological processes by which lipid accumulation confers a metabolic advantage to tumor-infiltrating Tregs (TI-Tregs) and amplifies their immunosuppressive functions. Furthermore, we will provide a summary of the driving effects of various metabolic regulators on the metabolic reprogramming of Tregs. Finally, we propose that targeting the lipid metabolism of TI-Tregs could be efficacious either alone or in conjunction with immune checkpoint therapy.

Abstract Phototherapy of deep tumors still suffers from many obstacles, such as limited near-infrared (NIR) tissue penetration depth and low accumulation efficiency within the target sites. Herein, stimuli-sensitive tumor-targeted photodynamic nanoparticles (STPNs) with persistent luminescence for the treatment of deep tumors are reported. Purpurin 18 (Pu18), a porphyrin derivative, is utilized as a photosensitizer to produce persistent luminescence in STPNs, while lanthanide-doped upconversion nanoparticles (UCNPs) exhibit bioimaging properties and possess high photostability that can enhance photosensitizer efficacy. STPNs are initially stimulated by NIR irradiation before intravenous administration and accumulate at the tumor site to enter the cells through the HER2 receptor. Due to Pu18 afterglow luminescence properties, STPNs can continuously generate ROS to inhibit NFκB nuclear translocation, leading to tumor cell apoptosis. Moreover, STPNs can be used for diagnostic purposes through MRI and intraoperative NIR navigation. STPNs exceptional antitumor properties combined the advantages of UCNPs and persistent luminescence, representing a promising phototherapeutic strategy for deep tumors.

With the advancement of scientific research, an increasing number of studies on metal nanozymes, particularly Au NPs, have been conducted. They possess glucose oxidase (GOD)-like activity and peroxidase (POD)-like activity, with GOD-like activity receiving the most attention. However, there is a lack of research and summary on future trends in Au NPs in biomedical field. Therefore, we conducted a study on the GOD-like activity of Au NPs based on 158 relevant publications downloaded from the Web of Science Core Collection between 2007 and 2023, using citation metrics, authors, nations, institutions, cited references, and keywords. We found that Au NPs were initially utilized for glucose biosensors, glucose detection in human serum, and the detection of other carbohydrates and proteins. Researchers have recently focused on its application in oncotherapy and diabetic wound treatment. In addition to being utilized to treat autoimmune illnesses, inflammation, and other diseases, Au NPs may eventually replace insulin and antibiotics. We anticipate that the use of Au NPs will increase in the future. We hope this study will serve as a guide for future researchers so that Au NPs can be applied more broadly and competently.

Abstract Background Reconstruction of damaged tissues requires both surface hemostasis and tissue bridging. Tissues with damage resulting from physical trauma or surgical treatments may have arbitrary surface topographies, making tissue bridging challenging. Methods This study proposes a tissue adhesive in the form of adhesive cryogel particles (ACPs) made from chitosan, acrylic acid, 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). The adhesion performance was examined by the 180-degree peel test to a collection of tissues including porcine heart, intestine, liver, muscle, and stomach. Cytotoxicity of ACPs was evaluated by cell proliferation of human normal liver cells (LO2) and human intestinal epithelial cells (Caco-2). The degree of inflammation and biodegradability were examined in dorsal subcutaneous rat models. The ability of ACPs to bridge irregular tissue defects was assessed using porcine heart, liver, and kidney as the ex vivo models. Furthermore, a model of repairing liver rupture in rats and an intestinal anastomosis in rabbits were established to verify the effectiveness, biocompatibility, and applicability in clinical surgery. Results ACPs are applicable to confined and irregular tissue defects, such as deep herringbone grooves in the parenchyma organs and annular sections in the cavernous organs. ACPs formed tough adhesion between tissues [(670.9 ± 50.1) J/m2 for the heart, (607.6 ± 30.0) J/m2 for the intestine, (473.7 ± 37.0) J/m2 for the liver, (186.1 ± 13.3) J/m2 for muscle, and (579.3 ± 32.3) J/m2 for the stomach]. ACPs showed considerable cytocompatibility in vitro study, with a high level of cell viability for 3 d [(98.8 ± 1.2) % for LO2 and (98.3 ± 1.6) % for Caco-2]. It has comparable inflammation repair in a ruptured rat liver (P = 0.58 compared with suture closure), the same with intestinal anastomosis in rabbits (P = 0.40 compared with suture anastomosis). Additionally, ACPs-based intestinal anastomosis (less than 30 s) was remarkably faster than the conventional suturing process (more than 10 min). When ACPs degrade after surgery, the tissues heal across the adhesion interface. Conclusions ACPs are promising as the adhesive for clinical operations and battlefield rescue, with the capability to bridge irregular tissue defects rapidly.

Abstract Background Penfluridol (PF) is an FDA-approved antipsychotic drug that has recently been shown to have anticancer activity. However, the anticancer effects and underlying mechanisms of PF are not well-established in gallbladder cancer (GBC). Methods The anticancer efficacy of PF on GBC was investigated via a series of cell functions experiments, including cell viability, colony formation, apoptosis assays, and so on. The corresponding signaling changes after PF treatment were explored by western blotting. Then, nude mice were utilized to study and test the anticancer activity of PF in vivo. Besides, glucose consumption and lactic production assays were used to detect the glycolysis alteration. Results In this study, we discovered that PF greatly inhibited the proliferation and invasion ability of GBC cells (GBCs). The glucose consumption and lactic generation ability of GBCs were dramatically elevated following PF treatment. Additionally, we discovered that inhibiting glycolysis could improve PF's anticancer efficacy. Further studies established that the activation of the AMPK/PFKFB3 signaling pathway medicated glycolysis after PF treatment. We proved mechanistically that inhibition of AMPK/PFKFB3 singling pathway mediated glycolysis was a potential synergetic strategy to improve the anticancer efficacy of PF on GBC. Conclusions By inhibiting AMPK, the anticancer effects of PF on GBCs were amplified. As a result, our investigations shed new light on the possibility of repurposing PF as an anticancer drug for GBC, and AMPK inhibition in combination with PF may represent a novel therapeutic strategy for GBC. Graphical abstract Video abstract

Abstract DNA molecules are subject to various lesions that can be detrimental to the cells. DNA damage response (DDR) pathways encompass a variety of mechanisms that cells employ in response to DNA damage. While DDR promotes genomic stability in normal cells, it also protects cancer cells from DNA lesions, particularly against exogenous DNA‐damaging agents. Therefore, DDR pathways can be exploited to account for resistance to chemotherapy and radiotherapy and have the potential to be targeted in cancer treatment. Apart from the poly (ADP‐ribose) polymerase (PARP) inhibitors used in BRCA‐mutant cancers, other DDR inhibitors are being developed and tested in clinical trials. Based on the synthetic lethality theory, combination therapies utilizing DDR inhibitors have been explored and are currently undergoing clinical trials, with promising results in cancer treatment. Combination therapies typically employ a DDR inhibitor to sensitize cancer cells to traditional chemotherapeutic agents, radiotherapy, immunotherapy, and even PARP inhibitors. Herein, we focus on recent advances in DDR inhibitor‐based combination therapies other than PARP inhibitors, explore the advantages and disadvantages of the strategies, and discuss the current challenges and future perspectives.

Abstract TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.

Background: The preoperative selection of patients with intermediate-stage hepatocellular carcinoma (HCC) who are likely to have an objective response to first transarterial chemoembolization (TACE) remains challenging. Objective: To develop and validate a clinical-radiomic model (CR model) for preoperatively predicting treatment response to first TACE in patients with intermediate-stage HCC. Methods: A total of 595 patients with intermediate-stage HCC were included in this retrospective study. A tumoral and peritumoral (10 mm) radiomic signature (TPR-signature) was constructed based on 3,404 radiomic features from 4 regions of interest. A predictive CR model based on TPR-signature and clinical factors was developed using multivariate logistic regression. Calibration curves and area under the receiver operating characteristic curves (AUCs) were used to evaluate the model’s performance. Results: The final CR model consisted of 5 independent predictors, including TPR-signature (p < 0.001), AFP (p = 0.004), Barcelona Clinic Liver Cancer System Stage B (BCLC B) subclassification (p = 0.01), tumor location (p = 0.039), and arterial hyperenhancement (p = 0.050). The internal and external validation results demonstrated the high-performance level of this model, with internal and external AUCs of 0.94 and 0.90, respectively. In addition, the predicted objective response via the CR model was associated with improved survival in the external validation cohort (hazard ratio: 2.43; 95% confidence interval: 1.60–3.69; p < 0.001). The predicted treatment response also allowed for significant discrimination between the Kaplan-Meier curves of each BCLC B subclassification. Conclusions: The CR model had an excellent performance in predicting the first TACE response in patients with intermediate-stage HCC and could provide a robust predictive tool to assist with the selection of patients for TACE.

Abstract Synthetic lethality is a lethal phenomenon in which the occurrence of a single genetic event is tolerable for cell survival, whereas the co-occurrence of multiple genetic events results in cell death. The main obstacle for synthetic lethality lies in the tumor biology heterogeneity and complexity, the inadequate understanding of synthetic lethal interactions, drug resistance, and the challenges regarding screening and clinical translation. Recently, DNA damage response inhibitors are being tested in various trials with promising results. This review will describe the current challenges, development, and opportunities for synthetic lethality in cancer therapy. The characterization of potential synthetic lethal interactions and novel technologies to develop a more effective targeted drug for cancer patients will be explored. Furthermore, this review will discuss the clinical development and drug resistance mechanisms of synthetic lethality in cancer therapy. The ultimate goal of this review is to guide clinicians at selecting patients that will receive the maximum benefits of DNA damage response inhibitors for cancer therapy.

Abstract Background It has been demonstrated that simultaneous resection of both primary colorectal lesion and metastatic hepatic lesion is a safe approach with low mortality and postoperative complication rates. However, there are some controversies over which kind of surgical approach is better. The aim of study was to compare the efficacy and safety of laparoscopic surgeries and open surgeries for simultaneous resection of colorectal cancer (CRC) and synchronous colorectal liver metastasis (SCRLM). Methods A systemic search of online database including PubMed, Web of Science, Cochrane Library, and Embase was performed until June 5, 2019. Intraoperative complications, postoperative complications, and long-term outcomes were synthesized by using STATA, version 15.0. Cumulative and single-arm meta-analyses were also conducted. Results It contained twelve studies with 616 patients (273 vs 343, laparoscopic surgery group and open surgery group, respectively) and manifested latest surgical results for the treatment of CRC and SCRLM. Among patients who underwent laparoscopic surgeries, they had lower rates of postoperative complications (OR = 0.66, 95% CI: 0.46 to 0.96, P = 0.028), less intraoperative blood loss (weight mean difference (WMD) = − 113.31, 95% CI: − 189.03 to − 37.59, P = 0.003), less time in the hospital and recovering after surgeries (WMD = − 2.70, 95% CI: − 3.99 to − 1.40, P = 0.000; WMD = − 3.20, 95% CI: − 5.06 to − 1.34, P = 0.001), but more operating time (WMD = 36.57, 95% CI: 7.80 to 65.35, P = 0.013). Additionally, there were no statistical significance between two kinds of surgical approaches in disease-free survival and overall survival. Moreover, cumulative meta-analysis indicated statistical difference in favor of laparoscopic surgery in terms of morbidity was firstly detected in the 12th study in 2018 (OR = 0.66, 95% CI: 0.46 to 0.96, P = 0.028) as the 95% CI narrowed. Conclusion Compared with open surgeries, laparoscopic surgeries are safer (postoperative complications and intraoperative blood loss) and more effective (length of hospital stay and postoperative stay), and it can be considered as the first option for management of SCRLM in high-volume laparoscopic centers. Trial registration CRD42020151176

Abstract Gallbladder cancer (GBC) is a rare but the most malignant type of biliary tract tumor. It is usually diagnosed at an advanced stage and conventional treatments are unsatisfactory. As a proteasome inhibitor, bortezomib (BTZ) exhibits excellent antitumor ability in GBC. However, the long‐term treatment efficacy is limited by its resistance, poor stability, and high toxicity. Herein, BTZ‐encapsulated pH‐responsive copolymeric nanoparticles with estrone (ES‐NP(BTZ; Ce6)) for GBC‐specific targeted therapy is reported. Due to the high estrogen receptor expression in GBC, ES‐NP(BTZ; Ce6) can rapidly enter the cells and accumulate near the nucleus via ES‐mediated endocytosis. Under acidic tumor microenvironment (TME) and 808 nm laser irradiation, BTZ is released and ROS is generated by Ce6 to destroy the “bounce‐back” response pathway proteins, such as DDI2 and p97, which can effectively inhibit proteasomes and increase apoptosis. Compared to the traditional treatment using BTZ monotherapy, ES‐NP(BTZ; Ce6) can significantly impede disease progression at lower BTZ concentrations and improve its resistance. Moreover, ES‐NP(BTZ; Ce6) demonstrates similar antitumor abilities in patient‐derived xenograft animal models and five other types of solid tumor cells, revealing its potential as a broad‐spectrum antitumor formulation.

BackgroundEnhanced recovery care could alleviate surgical stress and accelerate the recovery rates of patients. Previous studies showed the benefits of enhanced recovery after surgery program in liver surgery, but the exact role in laparoscopic hepatectomy is still unclear.AimWe aimed to perform a meta-analysis to evaluate the safety and efficacy of enhanced recovery after a surgery program in laparoscopic hepatectomy.MethodsThe relative studies from a specific search of PUBMED, EMBASE, OVID, and Cochrane database from June 2008 to February 2022 were selected and included in this meta-analysis. The primary outcomes included length of hospital stay, duration to functional recovery, and overall postoperative complication rate. The secondary outcomes included operative time, intraoperative blood loss, cost of hospitalization, readmission rate, Grade I complication rate, and Grade II–V complication rate.ResultsA total of six studies with 643 patients [enhanced recovery care (n = 274) vs. traditional care (n = 369)] were eligible for analysis. These comprised three randomized controlled trials and three retrospective studies. Enhanced recovery care group was associated with decreased hospital stay [standard mean difference (SMD) = −0.56, 95% confidence interval (CI) = −0.83~−0.28, p < 0.0001], shorter duration to functional recovery (SMD = −1.14, 95% CI = −1.92~−0.37, p = 0.004), and lower cost of hospitalization Mean Difference (MD) = −1,539.62, 95% CI = −1992.85~−1086.39, p < 0.00001). Moreover, a lower overall postoperative complication rate was observed in enhanced recovery care group [Risk ratio (RR) = 0.64, 95% CI = 0.51~0.80, p < 0.0001] as well as lower Grade II–V complication rate (RR = 0.55, 95% CI = 0.38~0.80, p = 0.002), while there was no significant difference in intraoperative blood loss (MD = −65.75, 95% CI = −158.47~26.97, p = 0.16), operative time (MD = −5.44, 95% CI = −43.46~32.58, p = 0.78), intraoperative blood transfusion rate [Odds ratio (OR) = 0.71, 95% CI = 0.41~1.22, p = 0.22], and Grade I complication rate (RR = 0.73, 95% CI = 0.53~1.03, p = 0.07).ConclusionEnhanced recovery care in laparoscopic hepatectomy should be recommended, because it is not only safe and effective, but also can accelerate the postoperative recovery and lighten the financial burden of patients.

ObjectivesThe primary laparoscopic approach (PLA) for T1b/T2 gallbladder cancer (GBC) remains contradicted. We aimed to compare the perioperative and long-term outcomes after PLA versus open approach (OA) for T1b/T2 GBC.MethodsPatients with resected T1b/T2 GBC were selected from our hospital between January 2011 and August 2018. Overall survival (OS), disease-free survival (DFS), and several secondary outcomes were used to evaluate safety and effectiveness. Subgroup analyses were performed to identify significant risk factors for OS/DFS in GBC patients undergoing PLA/OA.ResultsA total of 114 patients who underwent OA (n = 61) or PLA (n = 53) were included in the study. The percent of PLA cases was increased over time from 40.0% in 2011 to 70.0% in 2018 (p < 0.05). There was no significant difference in OS [hazard ratio (HR), 1.572; 95% confidence interval (CI), 0.866–2.855; p = 0.13] and DFS (HR, 1.225; 95% CI, 0.677–2.218; p = 0.49). No significance was found for intraoperative drainage placement (p = 0.253), intraoperative blood loss (p = 0.497), operation time (p = 0.105), postoperative hospitalization (p = 0.797), positive LNs (p = 0.494), total harvested LNs (p = 0.067), and recurrence rates (P = 0.334). Subgroup analyses demonstrated no significance of conversion rates after PLA (all p > 0.05). Patients undergoing PLA with good/poor OS would have similar recurrence rates (p = 0.402). Positive LNs (p = 0.032) and tumor differentiation (p = 0.048) were identified as risk factors for OS after PLA, while positive LNs (p = 0.005) was identified for OS after OA. Moreover, age (p = 0.013), gallbladder stone (p = 0.008), tumor size (p = 0.028), and positive LNs (p = 0.044) were potential risk factors for DFS after OA.ConclusionsPLA for T1b/T2 GBC was comparable to OA in terms of perioperative and long-term outcomes. Less positive LNs and well-differentiated tumors were independent predictors for better OS after PLA, and less positive LNs were also identified for better OS after OA. Additionally, younger age, without gallbladder stone, smaller tumor size, and less positive LNs were potential risk factors for better DFS after OA.

Abstract Background Pancreatic adenocarcinoma is a highly lethal malignancy. Neoadjuvant chemo(radio)therapy [NAC(R)T] is recommended to use for borderline resectable pancreatic cancer (BRPC) and high-risk resectable pancreatic cancer (RPC), but no high-level evidence exists. Methods We searched PubMed, EMBASE, Web of Science, and Cochrane library to identify trials comparing survival data of NAC(R)T with SF for RPC or BRPC. Overall survival (OS) was synthesized in analysis of all the patients (intention-to-treat [ITT] analysis) and resected patients respectively. Results The meta-analysis included 17 trials with 2286 participants. For BRPC, NAC(R)T improved OS both in ITT analysis (HR, 0.49; 95% CI, 0.37–0.65; P

A major obstacle for treatment of HCC is the inadequate efficacy and limitation of the available therapeutic options. Despite the recent advances in developing novel treatment options, HCC still remains one of the major causes of cancer morbidity and mortality around the world. Achieving effective treatment and eradication of HCC is a challenging task, however recent studies have shown that targeting Natural Killer cells, as major regulators of immune system, can help with the complete treatment of HCC, restoration of normal liver function and subsequently higher survival rate of HCC patients. Studies have shown that decrease in the frequency of NK cells, their dysfunction due to several factors such as dysregulation of receptors and their ligands, and imbalance of different types of inhibitory and stimulating microRNA expression is associated with higher rate of HCC progression and development, and poor survival outcome. Here in our review, we mainly focused on the importance of NK cells in HCC development and treatment.

BackgroundThe management of gallbladder cancer (GBC) patients with recurrence who need additional therapy or intensive follow-up remains controversial. Therefore, we aim to develop a nomogram to predict survival in GBC patients with recurrence after surgery.MethodsA total of 313 GBC patients with recurrence from our center was identified as a primary cohort, which were randomly divided into a training cohort (N = 209) and an internal validation cohort (N = 104). In addition, 105 patients from other centers were selected as an external validation cohort. Independent prognostic factors, identified by univariate and multivariable analysis, were used to construct a nomogram. The performance of this nomogram was measured using Harrell’s concordance index (C-index) and calibration curves.ResultsOur nomogram was established by four factors, including time-to-recurrence, site of recurrence, CA19-9 at recurrence, and treatment of recurrence. The C-index of this nomogram in the training, internal and external validation cohort was 0.871, 0.812, and 0.754, respectively. The calibration curves showed an optimal agreement between nomogram prediction and actual observation. Notably, this nomogram could accurately stratify patients into different risk subgroups, which allowed more significant distinction of Kaplan-Meier curves than that of using T category. The 3-year post-recurrence survival (PRS) rates in the low-, medium-, and high-risk subgroups from the external validation cohort were 53.3, 26.2, and 4.1%, respectively.ConclusionThis nomogram provides a tool to predict 1- and 3-year PRS rates in GBC patients with recurrence after surgery.

Background: Early-stage diagnosis and treatment can improve survival rates of liver cancer patients. Dynamic contrast-enhanced MRI provides the most comprehensive information for differential diagnosis of liver tumors. However, MRI diagnosis is affected by subjective experience, so deep learning may supply a new diagnostic strategy. We used convolutional neural networks (CNNs) to develop a deep learning system (DLS) to classify liver tumors based on enhanced MR images, unenhanced MR images, and clinical data including text and laboratory test results.Methods: Using data from 1,210 patients with liver tumors (N = 31,608 images), we trained CNNs to get seven-way classifiers, binary classifiers, and three-way malignancy-classifiers (Model A-Model G). Models were validated in an external independent extended cohort of 201 patients (N = 6,816 images). The area under receiver operating characteristic (ROC) curve (AUC) were compared across different models. We also compared the sensitivity and specificity of models with the performance of three experienced radiologists.Results: Deep learning achieves a performance on par with three experienced radiologists on classifying liver tumors in seven categories. Using only unenhanced images, CNN performs well in distinguishing malignant from benign liver tumors (AUC, 0.946; 95% CI 0.914–0.979 vs. 0.951; 0.919–0.982, P = 0.664). New CNN combining unenhanced images with clinical data greatly improved the performance of classifying malignancies as hepatocellular carcinoma (AUC, 0.985; 95% CI 0.960–1.000), metastatic tumors (0.998; 0.989–1.000), and other primary malignancies (0.963; 0.896–1.000), and the agreement with pathology was 91.9%.These models mined diagnostic information in unenhanced images and clinical data by deep-neural-network, which were different to previous methods that utilized enhanced images. The sensitivity and specificity of almost every category in these models reached the same high level compared to three experienced radiologists.Conclusion: Trained with data in various acquisition conditions, DLS that integrated these models could be used as an accurate and time-saving assisted-diagnostic strategy for liver tumors in clinical settings, even in the absence of contrast agents. DLS therefore has the potential to avoid contrast-related side effects and reduce economic costs associated with current standard MRI inspection practices for liver tumor patients.