Tumor Research Articles

Advanced neural network systems for analysis of blood-based biomarkers in metastatic disease detection

Neural network systems have become the gold provocative standard in blood-based biomarker analysis for metastatic disease diagnosis, providing higher sensitivity and specificity for early cancer detection. The lexical method also showed that recent developments in artificial intelligence and machine learning technologies allow for the complex interpretation of various types of biomarkers, such as circulating tumor cells, cell-free DNA, microRNAs, and proteins. Many biochemical patterns of biomarkers could be easily handled through sophisticated algorithms and depending on these active approaches in diagnosing metastatic outcomes more accurately at earlier stages. Literature analysis involved a targeted selection of scientific peer-reviewed articles dedicated to neural network utilization in blood-based biomarker screening for cancer. Doing a systematic evaluation critically assessed methodologies associated with artificial intelligence, types of biomarkers, methods of detecting biomarkers, and clinical validation strategies. Filtering was done based on several factors including the identification of new architectures for neural networks, new biomarker analysis methods, and clinical applications primarily focusing on the early detection of metastatic diseases. Analysis of reviewed studies showed a high diagnostic accuracy when neural network systems are used for biomarker analysis. Volumes in Cancer Computational Biology Vol reported that the machine learning models have achieved different sensitivity rates of over 90% including the ability to detect early-stage metastatic disease. The use of several categories of biomarkers and application-improved neural networks for their evaluation showed that the combined use of markers yields better diagnostic results than using single biomarkers. Neural network systems have significant potential to transform metastatic disease diagnosis using circulating biomarker detection. Using sophisticated computational models biomarker patterns are analyzed in detail and the diagnosis is made earlier, thus contributing to better treatment outcomes. Some complexities that are potential barriers include enforcing analysis protocols as standards, correcting and calibrating, and embracing routine technological practice. High-end artificial neural networks are the new frontier in blood-based biomarker analysis of metastatic disease diagnosis. Applying AI within the classic biomarker detection approach increases diagnostic reliability, detection timeliness, and the overall outlook for patient treatment. The advancement in neural network architectures as well as biomarker analysis techniques provides for further improvement in cancer diagnostics in the future.

Adaptive Immunity Determines the Cancer Treatment Outcome of Oncolytic Virus and Anti-PD-1.

The immune checkpoint inhibitor, anti-programmed death protein-1 (anti-PD-1), enhances adaptive immunity to kill tumor cells, and the oncolytic virus (OV) triggers innate immunity to clear the infected tumor cells. We create a mathematical model to investigate how the interaction between adaptive and innate immunities under OV and anti-PD-1 affects tumor reduction. For different immunity strength, we create the corresponding virtual baseline patients and cohort patients to decipher the major factors determining the treatment outcome. Global sensitivity analysis indicates that adaptive immunity has more control on the treatment outcome than innate immunity, and whether anti-PD-1 cancels out the OV treatment efficacy depends on the OV dosage and the balance between clearance of infected tumor cells and OV by T cells. The optimal OV infection rate and dosage suggest that OV treatment is more sensitive to adaptive immunity than innate immunity. Our model prediction also indicates that tumor reduction is more sensitive to anti-PD-1 efficacy as adaptive immunity becomes stronger, and anti-PD-1 trends to cancel out the OV treatment efficacy as innate immunity becomes stronger. Based on these results, the recommended treatment protocol for patients with different immunity strength can be determined.

An Oxidative Stress Nanoamplifier toEnhance the Efficacy of Cisplatin in Head and Neck Cancer.

Cisplatin (CP) is a first-line platinum-based drug used for the treatment of head and neck cancer. However, tumor cells can diminish the therapeutic effects of CP through the detoxification system mediated by glutathione (GSH) and the nucleotide excision repair (NER) pathway. Herein, we present a light-activable and pH-responsive oxidative stress nanoamplifier (FPLC@IR OSNA), comprising an amphiphilic compound (FPLC) with Fmoc-lysine acting as a connector between a nitroimidazole derivative and a pH-responsive cinnamaldehyde (CA) derivative, loaded with photosensitizer IR780. The acidic microenvironment of lysosome can trigger the release of CA to produce H2O2, which breaks down into oxygen, further improving the phototherapy efficacy mediated by IR780 irradiation. The consumption of oxygen during the phototherapy process induces hypoxia, prompting the reduction of nitroimidazole to aminoimidazole and leading to reduced GSH synthesis, enhancing tumor cell death induced by CP. Meanwhile, the accumulation of intracellular reactive oxygen species (ROS) during phototherapy attenuates the nuclear NER pathway, further augmenting the therapy effect of CP. This strategy, by combining FPLC@IR OSNA with laser and CP, significantly promotes the therapeutic effect in vitro, and notably inhibits tumor growth in both Cal27 cell line-derived xenograft models and patient-derived xenograft models.

CTCs Detection Methods In Vivo and In Vitro and Their Application in Tumor Immunotherapy.

Circulating tumor cells (CTCs) are tumor cells that detach from the primary tumor site and enter the bloodstream. They hold significant value for the early detection, diagnosis, and treatment of tumors. CTC detection methods can be classified into in vivo and in vitro techniques. Compared to traditional tumor detection methods, CTC detection causes less harm to the body and allows for earlier identification of malignant tumors, thereby enabling timely treatment and improving patient survival rates. In recent years, CTC detection has been widely used to assess the effectiveness of tumor immunotherapy. Dynamic monitoring of CTCs can help optimize clinical treatment strategies. This review summarizes the latest in vivo and in vitro detection methods for CTCs and discusses their applications in immunotherapy for various common tumors, aiming to provide better guidance and support for clinical practice.

Chlorin e6: a promising photosensitizer of anti-tumor and anti-inflammatory effects in PDT.

Photodynamic therapy (PDT) involves the activation of photosensitizers (PSs) by visible laser light at the target site to catalyze the production of reactive oxygen species, resulting in tumor cell death and blood vessel closure. The efficacy of PDT depends on the PSs, the amount of oxygen, and the intensity of the excitation laser. PSs have been extensively researched, and great efforts have been made to develop an ideal photosensitizer. Chlorin-e6 is an FDA-approved second-generation PSs that has attracted widespread research interest in the medical field, especially with respect to antitumor and anti-inflammatory activity. Chlorin-e6 possesses the advantages of a large absorption coefficient, high strength, low residue in the body, and relatively high safety and thus has promising application prospects. Here we review the use of chlorin-e6 in PDT and discuss the prospects of further development of this technology.

A quality-by-design approach to develop abemaciclib solid lipid nanoparticles for targeting breast cancer cell lines.

Abemaciclib (ABE) is an anticancer drug that suffers from low bioavailability and multidrug resistance. This study aims to develop ABE-loaded solid lipid nanoparticles (ABE-SLNs), which will enhance drug solubility and lead to increased cellular uptake and enhanced cytotoxicity when delivering tumor cells. Melt emulsification followed by ultrasonication was used as a method of preparation and Quality-by-Design (QbD) was utilized to optimize ABE-SLNs. The optimized ABE-SLNs consist of Precirol-ATO5 as a lipid and Brij-58 as a surfactant. The particle size, PDI value, and zeta potential of the optimized formulation were 170.4 ± 0.49 nm, 0.25 ± 0.014, and -26.4 ± 0.1 mV, respectively. It also showed sustained release behavior and a high entrapment efficiency of 79.96%. ABE-SLNs exhibited enhanced anticancer activity in the MDA-MB-231 and T47D breast cancer cell lines compared to pure ABE. In Caco-2human colonic cell lines, ABE-SLNs also showed increased cellular uptake. The use of QbD to achieve high entrapment efficiency and sustained release in ABE-SLNs, coupled with enhanced cellular uptake and cytotoxicity, represents a novel approach that could set a new standard for nanoparticle-based drug delivery systems.

Cinnamaldehyde-Based ROS-Responsive Polymeric Gene Vectors for Efficient Gene Delivery and Tumor Cell Growth Inhibition.

Reactive oxygen species (ROS)-sensitive polymers are extensively used in cancer therapies. However, the ROS levels in the tumor microenvironment are often insufficient to trigger an adequate therapeutic response. Herein, we report a cinnamaldehyde (CA)-based ROS-responsive cationic polymer (PCA) and demonstrate its high efficiency in gene delivery and tumor cell growth inhibition. CA could be released from the polymer via a ROS-sensitive thioacetal bond by endogenous ROS. The released CA successively induced more ROS accumulation through GSH depletion, and the positive feedback helped PCA to achieve self-accelerating degradation. Results proved that PCA/p53 complexes were efficient in depleting GSH, upregulating ROS levels, and gene transfection. Besides, PCA was also shown to be effective in delivering the therapeutic gene p53. More importantly, PCA/p53 complexes could significantly induce tumor cell growth suppression by a synergistic effect of PCA and p53, providing valuable insights into the design of self-amplifying ROS-responsive polymeric gene vectors.

The Extra-Tumoral Vaccine Effects of Apoptotic Bodies in the Advancement of Cancer Treatment.

The induction of apoptosis in tumor cells is a common target for the development of anti-tumor therapies; however, these therapies still leave patients at increased risk of disease recurrence. For example, apoptotic tumor cells can promote tumor growth and immune evasion via the secretion of metabolites, apoptotic extracellular vesicles, and induction of pro-tumorigenic macrophages. This paradox of apoptosis induction and the pro-tumorigenic effects of tumor cell apoptosis has begged the question of whether apoptosis is a suitable cancer therapy, and led to further explorations into other immunogenic cell death-based approaches. However, these strategies still face multiple challenges, the most critical of which is the tumor microenvironment. Contrary to the promotion of immune tolerance mediated by apoptotic tumor cells, apoptotic bodies with enriched tumor-related antigens have demonstrated great immunogenic potential, as evidenced by their ability to initiate systemic T-cell immune responses. These characteristics indicate that apoptotic body-based therapies could be ideal "in situ" extra-tumoral tumor vaccine candidates for the treatment of cancers, and further address the current issues with apoptosis-based or immunotherapy treatments. Although not yet tested clinically, apoptotic body-based vaccines have the potential to better treatment strategies and patient outcomes in the future.

HSP27/IL-6 axis promotes OSCC chemoresistance, invasion and migration by orchestrating macrophages via a positive feedback loop

Novel strategies to disrupt tumor progression have emerged from studying the interactions between tumor cells and tumor-associated macrophages (TAMs). However, the molecular mechanisms of interactions between tumor cells and TAMs underlying oral squamous cell carcinoma (OSCC) progression have not been fully elucidated. This study explored the molecular mechanism of the HSP27/IL-6 axis in OSCC chemoresistance, invasion, and migration. Here, we demonstrated the higher expression of HSP27 in OSCC cells. Paracrine HSP27 from OSCC cells enhanced chemoresistance, invasion, migration, and EMT in OSCC by inducing M2 polarization and IL-6 secretion in TAMs. HSP27 and IL-6 established a positive feedback loop between OSCC cells and M2 TAMs. TAMs-derived IL-6 orchestrated OSCC stemness and chemoresistance through upregulating β-catenin and CD44, and enhanced OSCC invasion, migration, and EMT via autocrine HSP27/TLR4 signaling. Collectively, HSP27/IL-6 axis facilitates OSCC chemoresistance, invasion, and migration by orchestrating macrophages through a positive feedback loop. We identify the regulatory mechanism underlying the interaction and crosstalk between OSCC cells and TAMs mediated by the HSP27/IL-6 axis. Targeting the HSP27/IL-6 axis could be a promising treatment strategy for OSCC patients, potentially controlling disease progression and improving prognosis and recurrence outcomes.Graphical Graphical Headlights1. HSP27/IL-6 axis promotes OSCC chemoresistance, invasion, and migration by promoting M2 polarization and IL-6 secretion of TAMs.2. HSP27/IL-6 mediates a positive feedback loop between OSCC cells and M2 TAMs.3. Targeting HSP27/IL-6 axis might be a promising treatment strategy for OSCC.

S100A13-driven interaction between pancreatic adenocarcinoma cells and cancer-associated fibroblasts promotes tumor progression through calcium signaling

BackgroundCancer-associated fibroblasts (CAFs) are key components of the pancreatic adenocarcinoma (PAAD) tumor microenvironment (TME), where they promote tumor progression and metastasis through immunosuppressive functions. Although significant progress has been made in understanding the crosstalk between cancer cells and CAFs, many underlying mechanisms remain unclear. Recent studies have highlighted the importance of calcium signaling in enhancing interactions between tumor cells and the surrounding stroma, with the S100 family of proteins serving as important regulators. While the roles of some S100 proteins have been extensively studied, others, such as S100A13, remain less well understood.MethodsBioinformatic analysis was employed to predict the pathogenic potential of CAFs and S100A13. Stable S100A13 knockdown CAFs were generated using a short hairpin RNA system. Cellular viability and apoptosis rates were evaluated through CCK-8 and flow cytometry tests, respectively. Additionally, the wound healing and migration assays were conducted to assess the invasive and metastatic capabilities. Transcriptome analysis was conducted to identify differential gene expression and associated signaling pathways in PAAD cells derived from an indirect culture system. Furthermore, the protumoral role of S100A13 in PAAD was further verified using both 3D bioprinting and cell line-based xenograft tumor models.ResultsIn this study, we identified a strong association between S100A13, a calcium-binding protein, and CAFs in PAAD. Gene expression analysis revealed that S100A13 was highly expressed in CAFs and correlated with poor prognosis. Knockdown of S100A13 in CAFs reduced the metastatic potential of PAAD cells. In addition, S100A13 depletion impaired cell motility and calcium signaling pathways within the TME. Furthermore, silencing S100A13 in CAFs markedly slowed PAAD progression in both tumor spheroids and Balb/c nude mice.ConclusionsTogether, our findings underscore the critical role of CAFs-derived S100A13 in PAAD progression and suggest that targeting S100A13 may offer a promising therapeutic strategy for PAAD.

Trends in Research of Odontogenic Keratocyst and Ameloblastoma.

Odontogenic keratocyst (OKC) and ameloblastoma (AM) are common jaw lesions with high bone-destructive potential and recurrence rates. Recent advancements in technology led to significant progress in understanding these conditions. Single-cell and spatial omics have improved insights into the tumor microenvironment and cellular heterogeneity in OKC and AM. Fibroblast subsets in OKC and tumor cell subsets in AM have been analyzed, revealing mechanisms behind their biological behaviors, including OKC's osteolytic features and AM's recurrence tendencies. Spatial transcriptomics studies of AM have identified engineered fibroblasts and osteoblasts contributing to matrix remodeling gene and oncogene expression at the invasion frontier, driving AM progression. Three-dimensional culture technologies such as organoid models have refined analysis of AM subtypes; uncovered the role of AM fibroblasts in promoting tumor cell proliferation and invasion; and identified signaling pathways such as FOSL1, BRD4, EZH2, and Wnt as potential therapeutic targets. Organoid models also served as preclinical platforms for testing potential therapies. Although preclinical models for AM exist, reliable in vitro and in vivo models for OKC remain scarce. Promising mimic models, including human embryonic stem cells-derived epithelial cells, human oral keratinocytes, human immortalized oral epithelial cells, and HaCaT keratinocytes, show promise, but the advancements in 3-dimensional culture technology are expected to lead to further breakthroughs in this area. Artificial intelligence, including machine learning and deep learning, has enhanced radiomics-based diagnostic accuracy, distinguishing OKC and AM beyond clinician capability. Pathomics-based models further predict OKC prognosis and differentiate AM from ameloblastic carcinoma. Clinical studies have shown positive outcomes with targeted therapies. In a study investigating SMO-targeted treatments for nevoid basal cell carcinoma syndrome, nearly all OKC lesions resolved in 3 patients. A recent clinical trial with neoadjuvant BRAF-targeted therapy for AM demonstrated promising radiologic responses, potentially enabling organ preservation. This review highlights recent advancements and trends in OKC and AM research, aiming to inspire further exploration and progress in these fields.

Dual-driven biodegradable nanomotors for enhanced cellular uptake.

Hybrid nano-sized motors with navigation and self-actuation capabilities have emerged as promising nanocarriers for a wide range of delivery, sensing, and diagnostic applications due to their unique ability to achieve controllable locomotion within a complex biological environment such as tissue. However, most current nanomotors typically operate using a single driving mode, whereas propulsion induced by both external and local stimuli could be more beneficial to achieve efficient motility in a biomedical setting. In this work, we present a hybrid nanomotor by functionalizing biodegradable stomatocytes with platinum nanoparticles (Pt NPs). These Pt NPs enable two distinct propulsion mechanisms. First, near-infrared (NIR) laser irradiation causes plasmonic heating, which, due to the asymmetric shape of the stomatocytes, creates a temperature gradient around the nanomotors. Second, the catalytic properties of the Pt NPs allow them to convert hydrogen peroxide into water and oxygen, generating a chemical gradient that serves as an additional driving force. Hydrogen peroxide is thereby locally produced from endogenous glucose by a co-encapsulated enzyme, glucose oxidase. The motile features are employed to achieve enhanced accumulation within tumor cells. This nanomotor design offers a versatile approach for developing dual stimuli-responsive nanomotors that operate more effectively in complex environments.

Prognostic models of immune-related cell death and stress unveil mechanisms driving macrophage phenotypic evolution in colorectal cancer

BackgroundTumor microenvironment (TME), particularly immune cell infiltration, programmed cell death (PCD) and stress, has increasingly become a focal point in colorectal cancer (CRC) treatment. Uncovering the intricate crosstalk between these factors can enhance our understanding of CRC, guide therapeutic strategies, and improve patient prognosis.MethodsWe constructed an immune-related cell death and stress (ICDS) prognostic model utilizing machine learning methodologies. Furthermore, we performed enrichment analyses and deconvolution algorithms to elucidate the complex interactions between immune cell infiltration and the processes of PCD and stress within a substantial array of transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus data base (GEO) related to CRC. Single-cell sequencing and biochemical experiments were used to validate the interaction between the model genes and programmed cell death in tumor cells.ResultsThe ICDS prognostic model exhibited robust predictive performance in seven independent cohorts, revealing an inverse correlation between model scores and patient prognosis. Meanwhile, the ICDS index was positively correlated with clinical stage. Model analysis indicated that patient subgroups with low ICDS index exhibited heightened immune activation features and elevated activity in PCD and stress pathways. Single-cell analysis further revealed that macrophages were the central drivers of immune characteristics underlying prognostic differences within the ICDS prognostic model. Pseudotime analysis and cellular experiments indicated that the model gene GAL3ST4 promotes the transition of macrophages toward an M2 pro-tumor phenotype. Furthermore, cell communication analysis and experimental validation revealed that the cuproptosis in tumor cells suppress GAL3ST4 expression, thereby inhibiting M2-like macrophage polarization.ConclusionIn summary, we constructed the ICDS prognostic model and uncovered the mechanism by which tumor cells downregulate GAL3ST4 expression via cuproptosis to inhibit M2-like macrophage polarization, providing new targets and biomarkers for CRC treatment and prognosis evaluation.

The Presence of Small-Size Circulating Tumor Cells Predicts Worse Prognosis in Non-Small Cell Lung Cancer Patients.

The Presence of Small-Size Circulating Tumor Cells Predicts Worse Prognosis in Non-Small Cell Lung Cancer Patients.

Halting Pancreatic Ductal Adenocarcinoma Progression and Metastasis by Neuron-Inhibitory Liposomes.

Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive malignancy. The occurrence of perineural invasion is associated with neuropathic pain and poor prognosis of PDAC, underscoring the active participation of nerves and their potential as therapeutic targets. Lidocaine is a local anesthetic with antitumor properties in some tumors in the clinic. Nevertheless, its clinical application in PDAC is constrained by the insufficient tumor accumulation and potential neurovirulence associated with a high-dose regimen. Here, a tumor microenvironment-targeted and -responsive liposome was constructed to deliver lidocaine for restraining PDAC growth through single nerve regulation. By conjugation of a collagen binding peptide, the pH-responsive liposomes accumulate in the extracellular matrix. The released lidocaine selectively reduces neurite length and density, thereby indirectly halting the progression and metastasis of PDAC in an orthotopic mouse model without noticeable adverse effects. This study highlights the potential of anesthetic-based nanomodulation of crosstalk between nerve and tumor cells for PDAC treatment.

Lymphatic vessel network injury reduces local tumor control despite preservation of the tumor-draining lymph node

The lymphatic system plays complex, often contradictory, roles in many cancers, including melanoma; these roles include contributions to tumor cell metastasis and immunosuppression in the tumor microenvironment as well as generation of antitumor immunity. Advancing our understanding of lymphatic vessel involvement in regulating tumor growth and immune response may provide new therapeutic targets or treatment plans to enhance the efficacy of existing therapies. We utilized a syngeneic murine melanoma model in which we surgically disrupted the lymphatic vessel network draining from the tumor to the tumor-draining lymph node (TDLN) while leaving the TDLN intact. Although transport of lymphatic-specific molecular weight tracers to the TDLN remains present after surgery, disruption of the tumor-draining lymphatic vessels results in decreased local tumor control, as reflected in an increase in the rate of tumor growth and reduction in effector-like T cell infiltration into the tumor. Our findings suggest that preservation of the functional tumor-draining lymphatic network may be essential in promoting a robust antitumor immune response.

Electrochemical capacitance-based aptasensor for HER2 detection.

The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) protein is specifically related to tumor cell proliferation in breast cancers. Its presence in biological serum samples indicates presence or progression of cancer, becoming a promise biomarker. However, their detection needs a simple and high accuracy platform. In this study, we report the develop and optimization of a simple highly sensitive electrochemical platform for HER2. Gold electrode surface was modified with a self-assembled monolayer composed by DNA aptamer, 6-(ferrocenyl) hexanethiol and 6-mercapto-1-hexanethiol. Electrochemical impedance spectroscopy was used to quantify the changes in capacitance on the interface due to the presence ferrocene, whether acting as a redox charge or its behavior under different HER2 concentration in PBS and undiluted human serum. As a result, the approach allows detection of HER2 with a limit of detection of 3.61 pg/mL, 12.28 nF sensitivity per decade and a linear range from 1 pM to 1 [Formula: see text]M in serum. This electrochemical aptasensor can be applied to different arrays for aptamer screening and has a significant importance to interaction study of biological systems.

Polyoxometalate-based injectable coacervate inhibits HCC metastasis after incomplete radiofrequency ablation via scavenging ROS

BackgroundIncomplete radiofrequency ablation (iRFA) stimulates residual hepatocellular carcinoma (HCC) metastasis, leading to a poor prognosis for patients. Therefore, it is imperative to develop an effective therapeutic strategy to prevent iRFA-induced HCC metastasis.ResultsOur study revealed that iRFA induced an abnormal increase in ROS levels within residual HCC, which enhanced tumor cell invasiveness and promoted macrophage M2 polarization, ultimately facilitating HCC metastasis. Molybdenum-based polyoxometalate (POM) is an excellent ROS-scavenging nanocluster, but its size is too small to be easily cleared by the kidneys, limiting its effectiveness in scavenging iRFA-induced ROS. To overcome this limitation, we synthesized an injectable POM-loaded coacervate delivery system named POM@Coa, which can sustainably scavenge iRFA-induced ROS by slowly releasing POM. POM@Coa markedly reduced HCC invasiveness, reversed macrophage polarization from M2 to M1, and promoted the infiltration and activation of CD8+ T cells, ultimately inhibiting HCC metastasis. Importantly, POM@Coa showed superior therapeutic efficacy to free POM in the absence of systemic toxicity.ConclusionsPOM@Coa exhibits the potential to decrease HCC invasiveness and activate anti-tumor immunity, opening up new avenues for the safe and effective treatment and prevention of HCC metastasis when combined with RFA.

A fractal–fractional order modeling approach to understanding stem cell-chemotherapy combinations for cancer

The main objective of this work is to study the mathematical model that combines stem cell therapy and chemotherapy for cancer cells. We study the model using the fractal fractional derivative with the Mittag-Leffler kernel. In the analytical part, we study the existence of the solution and its uniqueness, which was studied based on the fixed point theory. The equilibrium points were also studied and discussed after stem cell therapy, and the approximate solutions for the given model were obtained using the Adam Bashford method, which depends on interpolation with Lagrange polynomials. Finally, the model was simulated using the Mathematica software, and through the figures, we found that the components of the model approach the equilibrium point, which indicates the stability of the model at the equilibrium point. Also, the result of the numerical simulation and graphic for the concentration of cells over time indicate the effects of the therapies on the decay rate of tumor cells and the growth rate of effector cells to modify the cancer patient’s immune system. It is worth noting that we simulated all the model components with different fractional orders, confirming the effect of stem cell therapy and chemotherapy on the cells and the decay of cancer cells.

Targeting p38γ synergistically enhances sorafenib-induced cytotoxicity in hepatocellular carcinoma

Sorafenib (Sora) is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). It can significantly improve the survival rate of patients with advanced HCC, but it is prone to drug resistance during treatment, so the therapeutic effect is extremely limited. Here, we demonstrate that an elevated expression of protein kinase p38γ in hepatocellular carcinoma cells diminishes the tumor cells’ sensitivity to Sora. Pirfenidone (PFD) can augment Sora’s inhibitory effect on hepatocellular carcinoma by specifically targeting p38γ. Our study further uncovers that pirfenidone can synergistically boost the anti-hepatocellular carcinoma impact of Sora by impeding the autophagy heightened by p38γ. Taken together, our findings suggest that pirfenidone can work in concert with Sora to intensify its anti-tumor effect on hepatocellular carcinoma, thereby offering a novel therapeutic approach for Sora-mediated tumor treatment.Graphical PFD is an inhibitor of p38γ, which may affect the Beclin pathway by inhibiting the function of p38γ, thereby inhibiting the level of autophagy, and ultimately achieving the effect of sensitizing Sora. Created with BioRender.comGraphical HeadlightsKnockdown of p38γ sensitized the inhibitory effect of Sora on HCC cells;PFD synergistically enhances the anti-HCC effect of Sora by targeting p38γ;PFD sensitizes the anti-HCC effect of Sora by inhibiting autophagy.