2026年 · 第04卷第04期

Ferredoxin 1 (FDX1) is a small iron-sulfur (Fe-S) cluster protein localized to the mitochondria. It functions as an electron carrier in diverse metabolic pathways and is critically involved in the regulation of protein lipoylation Accumulating evidence indicates that FDX1 expression is frequently dysregulated across various cancer types. Its expression is significantly associated with cancer progression, prognosis, and tumor immune responses, suggesting its potential as a biomarker for cancer diagnosis, prognostic assessment, and prediction of immunotherapy response. Transcription factors, epigenetic modifications, and non-coding RNAs (ncRNAs) contribute to the aberrant expression of FDX1 in cancer cells. Mechanistic studies reveal that FDX1 protein influences cancer progression by modulating oncogenic signaling pathways, metabolic reprogramming, and tumor immunity: Notably, FDX1 serves as a central mediator of cuproptosis — a copper-dependent form of programmed cell death — highlighting its potential tumor-suppressive function. Therefore, FDX1 may exert dual roles in cancer by either promoting or inhibiting disease progression. Recently, several agents targeting FDX1 have exhibited promising therapeutic efficacy both in vitro and in vivo across diverse cancer models. In this review, we summarize the regulatory mechanisms governing of FDX1 expression and its functional roles in cancer progression, and further highlight its potential as a therapeutic target for cancer.

Mushrooms, recognized for their culinary and medicinal applications, are emerging as promising autophagy modulators in cancer therapy. Autophagy is cellular degradation triggered by organelle damage, protein aggregation, metabolic disturbances, or nutrient scarcity. It contributes to the suppression of early tumor development and the promotion of cancer cell survival at advanced stages. This review systematically assesses the current evidence on the anticancer potential of mushrooms and their bioactive compounds, focusing on the ability of these mushrooms and their bioactive compounds to modulate autophagy. The review lists over 18 mushroom species (e.g., Ganoderma lucidum [G. lucidum], Cordyceps, Phellinus) and 28 bioactive compounds (such as Ganoderic acid DM, Cordycepin, Hispidin) that affect autophagy, demonstrating efficacy against 15 cancer types, including colorectal, lung, breast, and liver cancers. Essential compounds modulate autophagy through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and Beclin-1 pathways, resulting in notable anticancer effects. G. lucidum extracts significantly reduced colorectal tumor growth by up to 60% in vivo. Additionally, Cordycepin induced autophagic cell death in lung cancer cells, with IC50 values as low as 25 μmol/L. The findings highlight the potential of mushrooms as low-toxicity adjuvants to conventional therapies, providing additional advantages such as immune modulation and antioxidant activity. Mushrooms and their bioactive components present promising avenues for cancer therapy through the modulation of autophagy. The context-dependent effects of autophagy, along with the limited clinical evidence, present considerable challenges. Future clinical trials must focus on developing standardized extracts and personalized approaches to effectively translate this preclinical potential into clinical practice.

Background: Globally, the incidence of breast cancer continues to rise; however, mortality rates are declining due to the growing effectiveness of targeted therapies and treatments. Overexpression of human epidermal growth factor receptor 2 (HER2) is seen in ~15% of breast cancers (termed HER2+). trastuzumab is the standard HER2-targeted therapy for HER2+ breast cancers in the adjuvant setting, and is increasingly being used as a neoadjuvant chemotherapy treatment (NACT or NAC). However, as well as the clinical impact, using drugs in a different treatment setting (including neoadjuvant therapy) has a financial impact. Economic evaluation of novel chemotherapeutic strategies can assess both clinical utility and cost-effectiveness, thereby informing and guiding healthcare resource allocation decisions. Currently, the cost, clinical outcomes, and cost-effectiveness of single-agent neoadjuvant trastuzumab remain underexplored. In this study, we evaluated the cost-effectiveness of trastuzumab administered as neoadjuvant therapy, adjuvant therapy, or a combination of both regimens (NACT/ACT). Methods: A 3-year retrospective observational comparative analysis was conducted to examine costs and health outcomes using clinicopathological data (treatment type, surgical procedure, breast cancer subtype) from a public hospital in Ireland. Overall, 192 non-metastatic, non-palliative HER2+ breast cancer patients (Luminal B HER2, and HER2+ [non-luminal]) were selected (151 adjuvant trastuzumab treated, 28 neoadjuvant trastuzumab treated, 13 NACT/ACT trastuzumab treated). The analysis estimated the cost of treatment (chemotherapy regimen, surgery type) and health outcomes, which were evaluated by analysis of survival data, and by calculating quality-adjusted life years (QALYs) and average cost-effectiveness ratios (ACERs). Multivariate regression analysis, using survival regression model techniques, was performed to evaluate associations between treatment types and total costs-adjusted by age, stage, grade, and subtype. A Cox proportional hazard model estimated the effect of treatment alternatives for time to disease-free survival (DFS). Results: Multivariate analysis demonstrated no significant difference in treatment cost (P = 0.318), surgery cost (P = 0.951), or DFS (P = 0.236) between the adjuvant and neoadjuvant trastuzumab treatment groups. A significantly higher treatment cost was observed in older patients (P = 0.011) and patients with Grade 3 tumours (P = 0.037). No significant difference in cost was found between the HER2 subtype groups (P = 0.129) or between disease stages (P = 0.710). No statistically significant difference in QALY was observed between adjuvant and neoadjuvant treatment groups (P = 0.296). Conclusion: Overall, while adjuvant trastuzumab remains the most cost-effective strategy for patients with HER2+ breast cancer, adopting a neoadjuvant trastuzumab approach does not appear to pose a significant economic disadvantage. Notably, higher treatment costs were observed among older patients, a finding with important financial implications for healthcare systems. These results highlight the need for careful evaluation to inform forthcoming age-related cancer policy updates.

Background: Glypican-3 (GPC3) is an important therapeutic target for chimeric antigen receptor (CAR) T-cell therapy in hepatocellular carcinoma (HCC). JWATM204 is a novel GPC3-targeted CAR T-cell therapy developed on the Antibody Redirected T Cells with Endogenous Modular Immune Signaling (ARTEMIS) T-cell platform, combining the high affinity and specificity of an anti-GPC3 monoclonal antibody with enhanced safety profiles. This Phase I study aimed to evaluate the safety and tolerability of JWATM204 in patients with advanced HCC. Methods: This single-arm, single-center, open-label Phase I dose-escalation study enrolled patients with GPC3-positive advanced HCC refractory to prior anti-tumor therapy. Three doses of JWATM204 were used: 1 × 108, 3 × 108, and 10 × 108 cells. The endpoints included dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetic parameters, and anti-tumor activity. Exploratory endpoints were predefined to evaluate potential biomarkers. Results: Six patients received an infusion of JWATM204, with two patients in each dose group. Only two instances of cytokine release syndrome (CRS) were observed, both were mild to moderate (Grade 2 and Grade 1, respectively), and resolved rapidly with standard management, demonstrating a favorable safety profile. No predefined DLTs were observed, and no cases of neurotoxicity or other serious treatment-related AEs occurred. Further dose escalation was not pursued due to strategic adjustments by collaborative partners and patient accrual challenges during the coronavirus disease 2019 (COVID-19) pandemic. Two patients achieved stable disease (SD; 33.3%; 95% confidence interval [CI], 5.9%-70.0%), while four experienced progressive disease (PD; 66.7%; 95% CI, 30.0%-94.1%), which yielded a disease control rate of 33.3% (95% CI, 5.9%-70.0%). As of the data cutoff date, one patient remained alive; three deaths were attributed to PD, one to COVID-19 co-infection, and one to intracranial hemorrhage. The median follow-up duration was 5.05 months (range, 3.00-25.90 months), with a median progression-free survival of 3.12 months (range, 2.07-5.77 months) and a median overall survival (OS) of 5.05 months (range, 3.00-25.90 months). The 6-month and 1-year OS rates were both 33.3% (95% CI, 5.9%-70.0%). Peripheral blood immune profiling suggested that patients with SD had higher proportions of natural killer (NK) cells both before and after treatment. RNA sequencing of pre-treatment tumor samples showed upregulated CRP and CYP2E1 expression in PD patients, which declined after therapy, suggesting potential links between inflammation and treatment response. Conclusions: JWATM204 demonstrated a favorable safety profile and showed preliminary anti-tumor activity in patients with advanced GPC3-positive HCC. Peripheral blood NK cell levels and tumor expression of CRP and CYP2E1 may serve as potential biomarkers for treatment response, providing a rationale for further optimization of CAR T-cell therapy in HCC.

Background: Acute myeloid leukemia (AML) is characterized by high relapse and mortality rates. Our previous investigation identified enoyl-CoA hydratase domain-containing protein 3 (ECHDC3) as being of prognostic significance in AML; however, the underlying pathways remain elusive. The intricate crosstalk among genetic abnormalities, metabolic pathways, and protein dysfunctions underpins the complexity contributing to its poor prognosis. Methods: ECHDC3 was knocked down by siRNA and subjected to RNA sequencing, chromatin immunoprecipitation (ChIP), and metabolomic assessments. Cell culture media were subjected to metabolomic assessments to evaluate changes in the bone marrow microenvironment. Mass spectrometry was conducted on bone marrow leukemia stem cells (CD34+) from chemotherapy-sensitive (S) and chemotherapy-resistant (R) patients. Additionally, untargeted metabolomic sequencing was performed on bone marrow supernatants from this patient cohort, and a combined proteomic-metabolomic analysis was conducted on the sequencing results from paired samples. Results: Knockdown of ECHDC3 significantly reduced the mitochondrial membrane potential (P < 0.0001), increased the mitochondrial gene expression MT-CO1 (P = 0.0367) and MT-CO2 (P = 0.0081), and enhanced manganese superoxide dismutase (MnSOD) activity (P = 0.0003). Significant differences were observed in choline metabolism in cancer (P = 0.0063), linoleic acid metabolism (P = 0.0160), and alpha-linolenic acid metabolism (P = 0.0250) between the R and S groups. Furthermore, correlation analysis of proteomic and metabolomic data suggested that choline and glycerophospholipid metabolism may play pivotal roles in the development of chemotherapy resistance in AML. Conclusions: ECHDC3 contributes to chemotherapy resistance in AML by regulating mitochondrial function, autophagy, and metabolic pathways. This study highlights ECHDC3 as a potential therapeutic target and offers insights into the development of AML treatments to overcome drug resistance.

Decitabine is widely used in the treatment of chronic myeloid neoplasms, potentially through its immunomodulatory effects on CD8+ T cells and natural killer (NK) cells. However, as decitabine is often administered in combination with other agents and at varying dosages, the specific effects of low-dose decitabine alone remain unclear. This study aimed to investigate whether low-dose decitabine alone influences immune cell populations. Twelve patients with chronic myeloid neoplasms, including eight with myelodysplastic syndrome, three with myelofibrosis, and one with chronic myelomonocytic leukemia (CMML), received intravenous decitabine at 5 mg/m2 for seven days per 28-day treatment cycle. Peripheral blood samples were collected before and after decitabine treatment to assess immune cell proportions and their potential correlation with clinical response. No significant differences were observed in natural killer cells, T cells, CD8+ T cells, CD4+ T cells, or regulatory T cells (Tregs) following decitabine treatment. However, the proportion of NKT-like cells significantly increased from 3.5% to 4.25% (P = 0.035). Among the three patients who received at least three cycles of decitabine, improvements in anemia and thrombocytopenia were observed in those with elevated NKT-like cell levels. These findings suggest that low-dose decitabine may enhance the NKT-like cell population, which may be associated with therapeutic responses in chronic myeloid neoplasms.

Xeroderma pigmentosum (XP)-associated internal malignancies are characterized by their rarity, early onset, atypical histological presentations, and poorly characterized genomic landscapes. In this study, we report the clinical, pathological, and molecular features of two rare XP-associated internal malignancies, focusing on their somatic mutation profiles. These tumors represented rare histological variants at their respective anatomical sites: an ovarian high-grade sex cord-stromal tumor (HG-SCST) with heterologous rhabdomyosarcomatous differentiation diagnosed in an 18-year-old female, harboring a homozygous XP complementation group C (XPC): NM_004628.5: c.1643_1644delTG (p.Val548Alafs*25) mutation and a renal leiomyosarcoma diagnosed in a 14-year-old male carrying a homozygous XPC: NM_004628.5:c.850G>T (p.Glu284*) mutation. Neither patient had a documented history of cutaneous malignancies. The patient with the ovarian tumor exhibited no response to chemotherapy and succumbed six months after diagnosis, whereas the patient with the renal leiomyosarcoma initially achieved a complete response but subsequently relapsed and died after five years and eight months of follow-up. The literature review identified only one previously reported case of renal leiomyosarcoma in a patient with XP and seven cases of XP-associated malignant ovarian tumors, including four SCSTs. In this study, targeted next-generation sequencing using the AmpliSeq for Illumina Cancer HotSpot Panel identified pathogenic mutations in canonical cancer driver genes: tumor protein p53 (TP53) NM_000546.6:c.730G>T (p.Gly244Cys) and platelet-derived growth factor receptor alpha (PDGFRA) NM_006206.6:c.2525A>T (p.Asp842Val) mutations in renal leiomyosarcoma and NRAS proto-oncogene, GTPase (NRAS) NM_002524.5:c.35G>T (p.Gly12Val) mutation in the ovarian tumor. These findings suggest a potential benefit of personalized therapies for XP patients with internal malignancies.

We report the case of a 73-year-old man with a 60-pack-year smoking history. He was diagnosed with a parotid malignancy in 2003 and underwent surgical resection. In 2008, definitive radiotherapy was administered due to tumor recurrence. In 2024, 16 years following radiotherapy, severe stenosis of the right carotid artery was identified, concomitant with severe coronary artery stenosis and calcification. Following multidisciplinary evaluation and percutaneous coronary intervention, his symptoms improved significantly, and he was discharged for regular outpatient follow-up.