Volume 27, Issue 6

Non-small cell lung cancer (NSCLC), which accounts for 85 % of all lung cancers, has been the focal point of cancer research for years and is associated with a high morbidity and mortality worldwide. Minimal residual disease (MRD) and expansion of drug-resistant clones after treatment are the main causes of recurrence in patients with NSCLC. These residual low-level diseases, coupled with mechanisms such as primary drug resistance, immune escape, bypass activation, and tissue-type transformation, have led to difficulties in anticancer therapy over the past decades. Recently, liquid biopsy has emerged as a powerful tool for early cancer detection and monitoring of treatment outcomes. Studies have demonstrated its potential in adjuvant cancer therapy and highlighted its advantages of low risk, high sensitivity, and other merits over other technologies. In this review, we assessed the detection samples and methods used in this technology and discussed the methods for detecting MRD and the latest progress in liquid biopsy for dynamically assessing the response of NSCLC to anticancer drugs, focusing on the application of liquid biopsies in NSCLC. Finally, we provide insights into future directions of liquid biopsies. We found that this technology enables the detection of undetectable MRD, assesses the efficacy of anticancer treatments, and ultimately reduces NSCLC recurrence, highlighting its potential therapeutic application.

Proton beam therapy (PBT) is a novel radiotherapy technique that provides highly conformal delivery of radiation dose to a tumor volume and less dose to neighboring healthy tissues, which depends on the Bragg peak. This dosimetric feature of PBT presents unique advantages for gastrointestinal (GI) malignancies in precise locations near dose-limiting structures in normal tissues, such as the heart and lungs. Because many GI tumors are in anatomically challenging sites, normal tissues may limit dosimetric efforts when treating those GI tumors with conventional photon-based approaches to tumor control. PBT presents a potential unique pathway to giving an increased dose to the tumor volume and minimizing treatment-related toxicity. Overall clinical outcome data give a glimpse into potential benefits of PBT, including minimized cardiopulmonary toxicity for esophageal cancer, improved preservation of liver functional reserve for hepatocellular carcinoma, and decreased gastrointestinal toxicity for pancreatic cancer. These would be especially meaningful aspects with multimodality therapy or in the setting of patients with limited functional reserve. The intent of this review is to summarize the recent clinical experience with PBT in the treatment of major GI malignancies, with a specific focus on clinical outcomes, toxicity, and other important technical considerations. Additionally, this review seeks to provide some insight into barriers to clinical use of PBT: high cost of PBT, limited availability, and the lack of large, randomized clinical trials. Future efforts will benefit from continuing to improve patient selection, elucidating possible synergistic effects with emerging systemic therapies, and producing higher levels of evidence to support broadening clinical application.

Cuproptosis represents a mechanistically distinct programmed cell death pathway divergent from canonical apoptosis, necrosis, and ferroptosis. This copper-dependent process critically modulates tumorigenesis, malignant progression, and clinical outcomes in neoplastic diseases. Non-coding RNAs (ncRNAs) modulate the expression of cuproptosis-related genes (CRGs) in tumors through the competing endogenous RNA mechanism. This regulation leads to copper ion accumulation, oxidative stress response, protein lipoylation, and ubiquitin-proteasome system activation, which eventually inhibit the occurrence and progression of tumors. The modulation of CRG expression by ncRNAs offers new perspectives for precision-targeted cancer therapy. This could potentially help develop more accurate and effective treatment approaches. Here, we review the mechanisms underlying cuproptosis, summarize the regulatory roles of ncRNAs in tumors, analyze the expression patterns of CRGs across multiple cancer types and their impact on patient prognosis, and elucidate the molecular mechanisms by which ncRNAs regulate cuproptosis in tumors. Furthermore, we provide clinical perspectives and highlight the potential opportunities for developing innovative therapeutic strategies for cancer.

Liver cancer remains a major global health burden due to its rising incidence and high mortality. Computed tomography (CT) is central to diagnosis and treatment planning, providing detailed anatomical and temporal information. In recent years, deep learning techniques, especially convolutional neural networks (CNNs) and Transformer-based models, have demonstrated strong potential in CT imaging, enabling automated tumor detection, segmentation, and characterization. These advances promise early diagnosis and precision medicine, though challenges such as limited annotated datasets, imaging variability, and barriers to clinical adoption remain. To capture recent progresses, we conducted a structured literature search in PubMed, IEEE Xplore, ScienceDirect, and SpringerLink for studies published between January 2021 and June 2025. Search terms combined three domains: deep learning/artificial intelligence (AI), liver cancer/hepatocellular carcinoma, and CT imaging. Eligible studies included original research applying deep learning to hepatic oncology CT tasks with quantitative evaluation, while the studies lacking methodological transparency or validation were excluded. Unlike prior broad reviews, this work specifically synthesizes CT-focused applications. We summarize key architectures, compare reported outcomes using metrics such as Dice coefficient, and discuss their clinical implications. Finally, we highlight gaps including reproducibility, dataset diversity and interpretability, and outline future opportunities in multimodal fusion and real-time deployment. This narrative review provides a concise and modality-focused perspective on the evolving role of deep learning in CT-based liver cancer management.

Lung cancer remains a leading cause of cancer-related death, and while both radiotherapy and immunotherapy have transformed its treatment, a strong biological rationale exists for combining these two modalities. This narrative review synthesizes current evidence, revealing a complex landscape. For early-stage disease, the concurrent use of stereotactic body radiotherapy (SBRT) and immune checkpoint inhibitors has yielded conflicting results; while some trials showed improved outcomes, others were prematurely terminated due to a lack of efficacy and increased toxicity. In contrast, for locally advanced non-small cell lung cancer (NSCLC), consolidation immunotherapy after chemoradiotherapy has become the standard of care, demonstrating durable survival benefits. These findings underscore the critical importance of treatment sequencing, as trials using concurrent immunotherapy in this setting have shown no benefit and higher toxicity. While the field shows significant promise, several key challenges persist, including determining optimal radiotherapy schedules, ideal treatment timing, and the development of reliable biomarkers to guide patient selection. Future research must focus on optimizing combination strategies and balancing efficacy with toxicity to improve patient outcomes.

Objectives Predictors of acute urinary retention after stereotactic body radiotherapy (SBRT) for localised prostate cancer remain undefined. This study aimed to evaluate the association between intravesical prostatic protrusion (IPP) and its occurrence. Methods This retrospective study analysed 210 patients with non-metastatic prostate cancer treated with SBRT (36.25 Gy) using CyberKnife. The distance from the apex of the prostate protruding towards the bladder to the plane connecting the bladder base, IPP, was measured using planned computed tomography. Acute urinary retention was graded according to the Common Terminology Criteria for Adverse Events, v5.0. Logistic regression and receiver operating characteristic analyses were performed to identify the predictors. Results Grade 2 acute urinary retention was present in 43 patients (20 %), with IPP being the only independent contributor in multivariate analysis (odds ratio [OR]=7.25; 95 % confidence interval [CI] 2.86–18.4; p<0.001). Urgent urinary catheterisation was required in five patients (2 %), of whom three required prolonged radiotherapy; IPP also contributed to this occurrence (p=0.004). An IPP cut-off of 0.8 cm predicted grade 2 acute urinary retention with moderate accuracy (area under the curve [AUC]=0.70), and a cut-off of 1.4 cm predicted the need for catheter placement with high accuracy (AUC=0.99). No patients experienced grade≥3 acute toxicity. Conclusion IPP is a simple, non-invasive, and strong independent predictor of acute urinary retention after SBRT for prostate cancer. Measures should be taken to prepare for unforeseen catheterisations, especially in cases with an IPP>1.4 cm. Advance information on the 7.25-fold higher odds of acute urinary retention aids decision-making.

Objectives Glutamine serves as a major fuel source for tumor cell proliferation while simultaneously playing an essential role in maintaining gastrointestinal health and immune function. Controversy exists regarding glutamine supplementation for cancer patients undergoing chemotherapy and radiation, with concerns that it may stimulate cancer growth. The main purpose of the study was to examine the effects of dietary glutamine supplementation (0.4 g/kg/day) on the growth of malignant gliomas, which utilize large amounts of glutamine to satisfy metabolic demands. Methods Glutamine supplementation was administered in food (25 mg glutamine/25 g of chow/cage/day) and water (1.0 mg/mL) until endpoint. Brain bioluminescence and subcutaneous tumor volumes were used to assess the effect of glutamine supplementation on the growth of the syngeneic VM-M3 and CT-2A preclinical models of glioma. Results Glutamine supplementation had no significant effect on the orthotopic growth of the VM-M3 or the CT-2A gliomas when compared to non-supplemented controls. However, glutamine supplementation significantly increased tumor volume by 28 % in the VM-M3 and by 166 % in CT-2A tumors when grown subcutaneously outside the central nervous system (CNS). Additionally, glutamine supplementation increased serum glutamine despite a localized decrease in intra-tumoral glutamine concentrations. Conclusions The results show that glutamine administration at 0.4 g/kg per day in mice did not affect orthotopic tumor growth in the brain but increased tumor growth subcutaneously. Hence, caution is warranted when considering chronic, high-dose glutamine supplementation in patients with glutamine-dependent malignancies. Further studies are needed to better understand the potential risks and benefits of glutamine supplementation in cancer therapy.

Objectives Most non-small-cell lung cancers (NSCLC) that harbour an epidermal growth factor receptor (EGFR) mutation are treated with afatinib. Resistance emerges in most patients, making treatment ineffective. Reports suggest intermittent treatment (IT) delays the emergence of resistance compared to standard-of-care continuous treatment (CT). Thus, this study aimed to investigate the efficacy of afatinib through both treatments in NSCLC in vitro . Methods The growth inhibition of afatinib was evaluated in mixed co-culture lines of HCC827 (sensitising with exon 19 deletion) and H1975 (resistant with L858R/T790M), with resistant percentages of 0.1% and 0.5 % treated with afatinib at 100 and 500 pM (pM). CT was treated for 96 h, while IT was treated for 24 h and was treatment-free for 72 h. They were assessed at 192 h with cell counting and qPCR with cell line-specific primers targeting exon 19 deletion and L858R, followed by images of fluorescent resistance. Results At 96 and 192 h, IT had a higher cell count than CT in both 0.1 % and 0.5 % resistance at 100 and 500 pM (p<0.05). The qPCR analysis showed the gene expression for resistant cells in IT was lower than in CT (p<0.05). However, nanomolar concentrations in patients’ pharmacokinetics resulted in resistance dominance and progression. Conclusions Overall, in both 0.1% and 0.5 % resistance in co-cultures, intermittent treatment allows a significant portion of viable sensitive cells to suppress the growth of resistant cells at concentrations of both 100 and 500 pM. Collectively, IT delays the emergence of de novo resistance with low resistance at specific concentrations. These findings offer the potential for utilising alternative treatment strategies as opposed to continuous treatment to improve therapeutic outcomes in NSCLC.

Objectives The urgency of screening patients for the potential benefit of immunotherapy has prompted explorations of predictive biomarkers or stratification for colorectal cancer (CRC). This study aims to explore the molecular subtypes associated with immune-related genes (IRGs) in CRC and to further elucidate the underlying molecular mechanisms. Methods IRGs were downloaded for non-negative matrix factorization (NMF) clustering. Kaplan-Meier survival analyses were used to assess survival differences. Gene set variation analysis was conducted for the exploration of potential biological mechanisms and pathways. The hub differentially expressed genes (DEGs) were selected via machine learning. Immunohistochemistry was performed to determine the expression of the hub gene and the infiltration of immune components. Results A preliminary classification of CRC subclasses was conducted through the NMF consensus clustering. Cluster 1 was found to exhibit worse overall survival and progression-free survival than Cluster 2. The two clusters demonstrated different enriched pathways, tumor immune scores, and differential gene expression. The intersection of screening characteristic genes pertained to two genes, SPP1 and GUCA2A. Immunohistochemistry indicated that SPP1 was overexpressed in CRC tissues. Patients with high SPP1 expression demonstrated a poorer prognosis, whether at the transcriptional or protein level. Immunohistochemistry revealed that high SPP1 expression was associated with more neutrophil and less CD8 + T cell infiltration. Conclusions NMF algorithm categorized CRC patients into two immunophenotypically distinct clusters with prognostic implications and a unique profile. SPP1 emerged as a crucial indicator for assessing tumor immune status, providing novel insights to enhance prognostic assessments and therapeutic strategies tailored to individual CRC patients.

Objectives While immunotherapy has improved survival outcomes in melanoma patients, effective biomarkers for predicting treatment responses and prognosis are still lacking. DNA base excision repair (BER) is closely linked to anti-tumor immunity, but the relationship between BER activity in melanoma and tumor-infiltrating lymphocytes (TILs) remains unclear. This study aims to analyze the association between BER activity in melanoma and T cells abundance. Methods In this study, a melanoma dataset from immune checkpoint blockers (ICBs) therapy was used to validate the relationship between TILs and immunotherapy response. Then, a single-cell sequencing dataset was used to investigate the association between melanoma with distinct biological characteristics and immune cell infiltration. Finally, immunohistochemical (IHC) analyses were performed to assess the correlation between the expression of Apurinic/apyrimidinic Endonuclease (APE1), a key enzyme in the BER pathway, and CD4+ T cell infiltration. Results A higher infiltration of CD4+ T cells was associated with better response and prognosis of ICBs treatment in melanoma (mPFS: 7.23 vs. 2.77 months, p<0.001; mOS: 32.3 vs. 10.1 months, n=121, p=0.012). Melanoma cells can be classified into four subtypes, and the BER subtype showed a significant positive correlation with CD4+ T cell infiltration (Pearson’s r=0.584, p=0.046). In the IHC assay, APE1 expression was positively correlated with CD4+ T cell abundance (Pearson’s r=0.58, n=89, p<0.001). Conclusions These findings suggest that BER activity is positively associated with CD4+ T cell infiltration, and APE1 expression may serve as a potential biomarker for evaluating melanoma treatment response and prognosis.

Objectives The study aims to discover biomarkers related to ferroptosis immunisation and predict their potential role in the prognosis of lung adenocarcinoma through the FER-IMMUscore model, so as to provide assistance for subsequent studies on ferroptosis and immunity in lung adenocarcinoma. Methods Relevant datasets were sourced from TCGA-LUAD, FerrDb, and ImmPort. Using LASSO regression, 11 ferroptosis-immunity-prognosis-related genes were analyzed to develop the FER-IMMUscore. Model validation employed GEO datasets (GSE68465, GSE30219) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immune cell infiltration was quantified via CIBERSORT, and tumor immune dysfunction/exclusion (TIDE) analysis was performed. Associations with Tumor Mutation Burden (TMB), genomic enrichment, clinical features, and immune microenvironment profiles were assessed. Results The model identified LIFR and NR5A2 as key genes. High-risk patients (stratified by FER-IMMUscore) had a poorer prognosis than the low-risk groups. Validation in GEO datasets confirmed the model’s prognostic value. qRT-PCR demonstrated differential expression of LIFR in lung adenocarcinoma. High-risk patients exhibited distinct immune microenvironments characterized by elevated immune evasion signatures, altered immune cell infiltration patterns, and higher TIDE scores. Significant correlations with TMB, genomic alterations, and clinical staging were observed. Conclusions The FER-IMMUscore model reliably stratifies lung adenocarcinoma patients into prognostic subgroups, with high-risk cases exhibiting distinct molecular profiles (LIFR/NR5A2), immunosuppressive microenvironments, and adverse clinical outcomes.

Objectives Early recurrence after surgical resection adversely affects long-term survival of hepatocellular carcinoma (HCC) patients. This study aims to develop and validate a novel predictive model for early recurrence of HCC after curative resection. Methods A retrospective study included 132 HCC patients who underwent surgical resection at the Second Affiliated Hospital of Anhui Medical University between October 2018 and May 2021. Clinical and pathological features were evaluated to assess parameters independently linked with early recurrence. Associations between possible risk factors and early recurrence were evaluated using multivariate logistic regression models. Results Of the 132 individuals, 48 (36.36 %) had early recurrence. Multivariate analysis identified AFP level≥400 ng/mL (OR=2.603, 95 % CI: 1.056–6.587, p=0.039), portal hypertension (OR=3.556, 95 % CI: 1.195–11.049, p=0.024), tumor size>10 cm (OR=5.036, 95 % CI: 1.264–23.237, p=0.027), albumin<35 g/L (OR=0.127, 95 % CI: 0.041–0.353, p<0.001), and GGT≥50 U/L (OR=2.172, 95 % CI: 0.863–5.612, p=0.042) were independently predictive of early recurrence. Conclusions Early recurrence after HCC resection is associated with high AFP levels, presence of portal hypertension, larger tumor size, reduced serum albumin, and elevated GGT levels. Monitoring of these signs after surgery may help identify patients at a higher risk more quickly, allowing for earlier intervention and potentially better long-term outcomes.

Objectives Synthetic lethality-based cancer therapy, particularly using PARP inhibitors, faces resistance challenges. This study aims to explore the role of gene-specific transcripts due to alternative splicing in PARP inhibitor resistance. Methods This study conducted transcript-level correlation analyses using CCLE and GDSC databases to identify associations between PARP2 splice variants and sensitivity to PARP inhibitors. This study validated the findings through in vitro overexpression experiments in MDA-MB-231 breast cancer cells and organoid models derived from ovarian cancer patients. Cytotoxicity assays were performed to assess olaparib sensitivity, and RNA sequencing was applied to examine transcriptomic changes. Functional enrichment analyses and clinical prognosis evaluations were conducted using TCGA datasets. Results The PARP2 splice variant ENST00000539930 showed a strong correlation with PARP inhibitors sensitivity, outperforming total PARP2 gene expression. Overexpression of ENST00000539930 in MDA-MB-231 cells significantly increased sensitivity to olaparib. Patient-derived ovarian cancer organoids confirmed this correlation (r=−0.43, p=0.04). Transcriptomic analysis revealed that ENST00000539930 expression was associated with activation of RNA splicing and inhibition of DNA repair pathways. Clinically, high ENST00000539930 expression predicted improved survival in breast, ovarian, and pancreatic cancer cohorts (HR=0.62–0.71, p<0.05). Conclusions ENST00000539930 is a splice variant of PARP2 that predicts enhanced sensitivity to PARP inhibitors and favorable clinical outcomes. This study highlights the potential of transcript-specific biomarkers and the importance of alternative splicing in cancer therapy response.

Objectives Vacuolar protein sorting-associated protein VTA1 homolog (VTA1) encodes a factor involved in multivesicular body trafficking. This investigation sought to determine if VTA1 might function as a diagnostic indicator, a standalone prognostic element, and a potential therapeutic target in breast cancer. Methods We performed a pan-cancer analysis of VTA1 expression using TCGA data from 33 cancer types and assessed immune infiltration with TIMER2.0. Breast cancer data from TCGA and Gene Expression Omnibus (GEO) database were collected to complete the difference analysis, clinical feature correlation, prognosis analysis, enrichment analysis, and tumor microenvironment score analysis of VTA1 in BRCA. The presence of VTA1 in BRCA cells was verified by Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR), Western Blot (WB), and Immunohistochemistry (IHC). Results VTA1 expression was markedly elevated in breast cancer. Elevated levels were significantly linked to worse overall survival (OS). (hazard ratio [HR] = 1.791, 95 % CI: 1.206–2.659, p<0.01) and recurrence-free survival (RFS), indicating that VTA1 is an independent prognostic factor. In the tumor immune microenvironment, high VTA1 expression correlated with increased infiltration of myeloid and resting immune cells but decreased effector/activated immune cells, suggesting poor prognosis. Conclusions VTA1 is a promising prognostic indicator for various cancers, particularly in breast cancer. The expression of VTA1 is markedly elevated in breast cancer tissues relative to the adjacent normal tissues. Clinical analyses further suggest that VTA1 functions as an independent indicator associated with unfavorable outcomes in breast cancer. These findings imply that VTA1 may serve as a promising biomarker for diagnosis, therapeutic guidance, and survival prediction.

Objectives Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, and its pathogenesis is closely associated with dysregulated cell death. This study aims to elucidate the role of the ubiquitin-specific protease 24 (USP24) in ccRCC progression and its molecular mechanisms. Methods Multi-omics data from the TCGA, GEO, and HPA databases were integrated to analyse USP24 expression levels and their clinical significance in ccRCC. The specific mechanism of interaction between USP24 and voltage-dependent anion channel 2 (VDAC2) was validated through co-immunoprecipitation, mass spectrometry analysis, molecular docking, and site-directed mutagenesis. In vitro functional assays – including deubiquitination assays, flow cytometry analysis of apoptosis, and assessment of ferroptosis-related markers – verified USP24’s inhibitory effect on ccRCC. Results USP24 was significantly downregulated in ccRCC tissues and cell lines, with its low expression correlated with poor patient prognosis (hazard ratio [HR]=0.57, p<0.001), suggesting its potential utility as a prognostic indicator. Mechanistic studies revealed that USP24 directly binds VDAC2 and removes its ubiquitinylation at position 277, thereby stabilizing the VDAC2 protein. This stabilizing effect promotes apoptosis and ferroptosis in ccRCC cells, and reactivating this pathway may serve as a viable therapeutic strategy for ccRCC. Single-cell RNA sequencing analysis further confirmed the co-expression of USP24 and VDAC2 in renal tubular epithelial cells. Conclusions This study reveals that the USP24-VDAC2 axis exerts key tumour-suppressive functions by promoting apoptosis and ferroptosis, thereby inhibiting ccRCC progression. Targeting this axis may provide novel therapeutic strategies for ccRCC.

Objectives The factors associated with bone marrow metastasis (BMM) in breast cancer (BC) remain poorly understood. This study aimed to investigate the clinicopathological characteristics, prognosis, and therapeutic implications of BC with BMM. Methods This study included patients with BC who underwent bone marrow biopsy for suspected BMM at The First Hospital of Jilin University between January 2010 and August 2018. Patients were classified into BMM and non-BMM groups based on biopsy results. The primary outcome was overall survival (OS), assessed using the Kaplan–Meier method and analyzed with Cox regression. Results Of the 106 patients evaluated, 70 had confirmed BMM. All patients with BMM exhibited bone metastases, with the majority (90 %) displaying bone as the initial site of distant metastasis. A significant association was found between BMM and an increased number of metastatic sites (p=0.004). The median OS after bone marrow biopsy was 5.93 months for BMM patients and 10.63 months for non-BMM patients (p=0.429). Cox regression analysis showed that patients continuing systemic therapy had a markedly longer median OS (11 vs. 2.07 months, p<0.001). Chemotherapy yielded a higher survival benefit compared to other agents (12.23 vs. 3.13 months, p=0.001), and the effectiveness of combination chemotherapy surpassed that of mono-chemotherapy (median OS 15.93 vs. 5.8 months, p=0.049). Conclusions BC with BMM is characterized by concurrent bone metastases and a higher number of metastatic sites. Although BMM is associated with a poorer prognosis, systemic therapy, particularly combined chemotherapy, significantly enhances survival outcomes.

Immunotherapy with anti-programmed cell death protein 1 (PD-1) is a promising anticancer treatment. However, only a minority of patients benefit from anti-PD-1 antibodies. Therefore, identifying the corresponding predictive factors is crucial. Emerging studies have found that the mitochondrial status of immune cells determines tumor response to anti-PD-1 antibodies. Here, we propose a novel hypothesis, based on recent experimental evidence, introducing cancer cell mitochondrial content as a new predictive factor for response to anti-PD-1 immunotherapy. A recent experiment on triple-negative breast cancer cells demonstrated that chemotherapy-induced ATPase family AAA domain–containing protein 3A (ATAD3A) expression levels regulate programmed death ligand-1 (PD-L1) on cancer cells. Accordingly, high ATAD3A expression is associated with high PD-L1 expression, poor tumor response to immunotherapy, and poor overall survival. In contrast, clinical evidence shows that high PD-L1 expression is associated with better response to immunotherapy and improved survival. This discrepancy forms the basis of our hypothesis. We propose that ATAD3A overexpression promotes poor response to anti-PD-1 therapy not by upregulating PD-L1, but by supporting mitochondrial metabolism. ATAD3A is a mitochondrial protein that maintains mitochondrial function and structure under endoplasmic reticulum stress. Therefore, mitochondrial biogenesis may serve as a novel predictive factor for response to anti-PD-(L)1 antibodies.

Mitochondrial cristae pathobiology, involving partial or total cristolysis, is a hallmark of human and mammalian cancer. This feature represents the basis of metabolic dysfunction in neoplastic cells. Consequently, most cancer cells with mitochondrial cristae defects would be incapable of producing adequate amounts of energy through oxidative phosphorylation. ATP production through increased glucose-driven cytosolic and glutamine-driven mitochondrial substrate-level phosphorylation thus becomes necessary to compensate for OxPhos insufficiency. The aim of this article is to offer a brief perspective on the link between the mitochondrial cristae pathobiology and the metabolic reprogramming in cancer cells, whose origin is linked to chronic mitochondrial cristae lesion (named α) and its eventual resolution by means of a progressive and continuous process of tumor cell death (named ω), induced by metabolic targeting. Dietary and pharmacological metabolic therapies that restrict the utilization of glucose and glutamine in tumor cells while elevating circulating ketone bodies represent a non-toxic therapeutic strategy for cancer management. Metabolic therapy can induce a persistent state of energy stress with a consequent increase in tumor cell death and reduction of tumor mass while improving the energy efficiency of non-neoplastic cells. Recent clinical studies suggest that ketogenic metabolic therapies may be therapeutically useful and well-tolerated in the long term.

Ma et al. identified sterol O-acyltransferase 1 (SOAT1) as a key metabolic-immune node in hepatocellular carcinoma (HCC). These authors revealed that SOAT1 loss induced ROS-driven ER stress that activates IKK β -NF- κ B signaling and up-regulates the chemokines CXCL16, CXCL12, and CX3CL1, which reshape the tumor microenvironment to favor antigen presentation and T-cell cytotoxicity. Consequently, SOAT1 inhibition synergizes with anti-PD-1 therapy, underscoring SOAT1 as a tractable target to combine metabolic disruption with immune activation in HCC. This study establishes SOAT1 as a key metabolic-immune node that may potentially impact the field of HCC treatment. SOAT1 inhibitors have the potential to act synergistically with additional immune checkpoint inhibitors beyond anti-PD-1, including anti-CTLA-4, anti-LAG-3, or anti-TIM-3 antibodies, as the metabolic reprogramming resulting from SOAT1 inhibition significantly modifies the tumor microenvironment. Moreover, SOAT1 inhibition may be integrated with locoregional therapies frequently employed in the management of hepatocellular carcinoma, such as trans arterial chemoembolization or radioembolization. Finally, SOAT1 expression levels or lipid metabolic signatures may function as biomarkers for patient stratification in forthcoming clinical trials, facilitating the development of more tailored combination therapy strategies. However, assessment of drug toxicity and careful selection of patients are potential challenges that may impede timely clinical implementation.