Antimetabolites, chemotherapy targeting nucleotide biosynthesis, are among the oldest and most widely used cancer treatments, yet resistance remains a daunting barrier, especially in the fight against B cell lymphomas. However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model. A similar mechanism occurred after long treatment of human B cell lymphoma cells with the chemotherapeutic purine synthesis inhibitor 6-mercaptopurine (6MP). Mechanistically, we demonstrated that dipeptides containing essential amino acids activated the growth and survival mTOR complex 1 (mTORC1) signaling pathway. Notably, SLC15A3 specifically interacted with mTOR on the lysosome, boosting mTORC1 activity selectively in resistant lymphoma cells but not in parental cancer cells. Silencing SLC15A3 diminished mTORC1 activity and restored resistant lymphoma sensitivity to 6MP. Strikingly, resistant lymphomas, but not primary tumors, exhibited heightened sensitivity to the clinical mTOR inhibitor, rapamycin, in culture and in vivo. We extended these findings in human lymphoma biopsies, which revealed increased SLC15A3 expression following antimetabolite therapy. Together, our study uncovered a metabolic adaptation that fuels cancer resistance to nucleotide deficiency and positions the mTORC1 inhibitor, rapamycin, as a potential therapeutic strategy for transforming the management of chemotherapy-resistant lymphomas.

Gynecological malignancies represent a significant global health burden for women worldwide. Tumor-associated macrophages (TAMs), as a critical component of the immune system, play a pivotal role within the tumor microenvironment (TME). Modulating signaling pathways in the TME can promote the polarization of TAMs toward the M1 phenotype, thereby enhancing anti-tumor effects and suppressing tumor growth and metastasis. The rapid advancement of nano-drug delivery systems (NDDSs) has expanded the potential for clinical translation of immunotherapies targeting TAMs. Our review provides an overview of the latest research progress on TAMs polarization-related signaling pathways and the use of NDDSs for targeted TAMs therapy in gynecological malignancies. Concurrently, the challenges encountered during the clinical translation of these therapeutic measures and future directions are discussed, aiming to provide novel insights for the immunotherapy of gynecological malignancies.

Autophagy plays paradoxical roles in breast cancer, functioning as both a stress-adaptive survival mechanism and a tumor-suppressive process depending on cellular and microenvironmental context. However, the molecular logic governing this functional duality has remained incompletely understood. Emerging evidence identifies the Wnt/β-catenin-mTOR axis as a central signaling hub that integrates proliferative, metabolic, and developmental cues to determine the directionality and functional outcome of autophagy. Aberrant activation of Wnt/β-catenin signaling reinforces mTOR activity, suppresses autophagic flux, and promotes stemness, epithelial-mesenchymal transition, therapeutic resistance, and immune evasion. Conversely, inhibition of Wnt signaling can relieve mTOR-mediated autophagy repression, leading to context-dependent induction of cytotoxic or cytostatic autophagy. Beyond tumor cell-intrinsic effects, Wnt-mTOR-autophagy crosstalk critically shapes the tumor immune microenvironment. In particular, SOCS3 deficiency-driven activation of Wnt/mTOR signaling represses autophagy in early-stage myeloid-derived suppressor cells, thereby sustaining their survival and immunosuppressive function. This mechanism highlights autophagy as an immunometabolic fate switch that governs myeloid cell persistence and antitumor immune suppression. Importantly, autophagy also feeds back to restrain Wnt signaling through selective degradation of pathway components, establishing dynamic regulatory loops that fine-tune oncogenic signaling output. In this review, we synthesize current evidence to delineate the bidirectional crosstalk between Wnt/β-catenin signaling, mTOR activity, and autophagy in breast cancer. We discuss how this integrated network governs tumor cell states, immune suppression, and therapeutic responsiveness, and propose a biomarker-driven, context-specific framework for autophagy modulation. By integrating signaling, autophagy flux, and myeloid immune status, precision targeting of the Wnt-mTOR-autophagy axis may offer new opportunities to overcome therapeutic resistance and improve clinical outcomes in breast cancer.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor prognosis and significant heterogeneity. Lipid metabolic reprogramming is a key hallmark of cancer, yet its systemic characterization and clinical relevance in AML remain largely unexplored.

Multi-omics data were integrated, including one single-cell RNA-seq dataset and bulk transcriptomes from nine AML cohorts. Lipid metabolism activity was assessed using GSVA. Consensus clustering based on lipid metabolism pathways identified molecular subtypes. A lipid metabolism-related prognostic signature (LMRS) was constructed via machine learning algorithms and validated across nine independent cohorts. Functional validation was performed in AML cell lines using GSTO1 inhibition.

Single-cell analysis revealed significant upregulation of lipid metabolism pathways in AML malignant cells, particularly in progenitor-like subpopulations. Three lipid metabolism-based subtypes (C1-C3) were identified, with the C3 subtype exhibiting the highest metabolic activity, an immunosuppressive microenvironment, and the worst prognosis. A robust nine-gene LMRS model was developed, which effectively stratified patients into high- and low-risk groups with distinct survival outcomes. LMRS demonstrated superior predictive accuracy over existing models, was independently prognostic, and correlated with chemotherapy and immunotherapy resistance. Inhibition of GSTO1 significantly induced apoptosis and ROS production in AML cells.

This study comprehensively defines lipid metabolic heterogeneity in AML, establishes a clinically applicable prognostic signature, and underscores lipid metabolism as a key driver of AML progression and immunosuppression. Targeting lipid metabolism, particularly through GSTO1 inhibition, represents a promising therapeutic strategy.

Patients with high-grade B-cell lymphoma (HGBCL), who are in early relapse or primary refractory, always have poor outcomes. Even intensive chemotherapy or CAR-T cell therapy is not always the best solution. Here is a case of refractory high-grade B-cell lymphoma with MYC, BCL2, and BCL6 rearrangements (triple-hit HGBCL), who achieved complete metabolic remission (CMR) following six cycles of glofitamab monotherapy induction and followed by autologous stem cell transplantation (ASCT) consolidation. The patient has achieved a sustained CMR and a progression-free survival (PFS) of 25 months (ongoing) from progression. Hepatitis B virus (HBV) seroconversion occurred during ASCT before stem cell engraftment, and was effectively suppressed with entecavir. Immune function was monitored in our case by flow cytometry. Downregulation of PD-1 expression on T cells and a reduced proportion of regulatory T cells (Tregs) were observed, consistent with fully activated immune function, which may explain why the patient responded rapidly and maintained durable efficacy. Immune analysis also exhibited B cell subset exhaustion and a disrupted naïve/memory T cell ratio which suggested an immunosenescence phenotype. It is speculated that an over activation of immune function promotes immunosenescence following bispecific antibody therapy, this needs attention. This case highlights the potential of glofitamab induction followed by ASCT consolidation to achieve durable remission in aggressive triple-hit HGBCL. The immune function after bispecific antibody treatment should be monitored and needs further investigation.

Although immune checkpoint blockade (ICB) has changed treatment strategies for gastric adenocarcinoma (STAD), many patients show primary resistance. Tumor-intrinsic transcriptional heterogeneity may contribute to immune escape, but the malignant-cell programs and candidate biomarkers linked to this process remain incompletely defined. Here, we integrated single-cell transcriptomic profiles of 162,116 cells from 35 STAD samples with multiple bulk transcriptomic cohorts to characterize malignant-cell regulatory programs. Non-negative matrix factorization identified meta-program 2 (MP2), a malignant-cell program closely associated with immune-escape signatures. Through integrated co-expression analysis and machine-learning-based prioritization, RNASE1 was identified as an MP2-related candidate biomarker. High RNASE1 expression was associated with poor survival, higher immune and stromal scores, increased immune-checkpoint expression, and enrichment of ICB-response-related transcriptomic signatures. In vitro RNASE1 knockdown reduced STAD cell proliferation, migration, and invasion, supporting a functional contribution to malignant cellular phenotypes. Together, these findings suggest that RNASE1 is an immune-evasion-associated biomarker with potential value for prognosis and ICB-response stratification in STAD, while prospective clinical and in vivo validation remain necessary.

Primary breast lymphoma (PBL) is an exceptionally rare entity, accounting for only 0.3-0.5% of all breast lymphomas. The majority of reported cases are diffuse large B- cell lymphoma. Clinical and imaging findings often mimic breast carcinoma, and diagnosis is usually confirmed incidentally by biopsy. Recurrent breast abscesses in non-lactating women or in men should raise suspicion of underlying malignancy.

We report the case of a 55-year-old non-lactating woman who presented to the surgical clinic with a non-healing wound following the incision and drainage of a recurrent breast abscess. A second excisional biopsy revealed primary classical Hodgkin lymphoma of the right breast, mixed cellularity subtype. The patient was treated with the BV-AD regimen, resulting in an excellent clinical response and complete wound healing.

This case highlights the importance of considering malignant etiologies, including rare lymphomas, in patients with recurrent breast abscesses. It underscores the diagnostic challenges posed by overlapping features with breast carcinoma and contributes to the limited literature on primary classical Hodgkin lymphoma of the breast.

Extramedullary hematopoiesis (EMH) is a compensatory process that supplements defective hematopoiesis and is frequently observed in myeloproliferative neoplasms (MPNs). Liver, spleen, and lymph nodes are the most common sites of EMH, whereas its occurrence in the intracranial space is extremely rare. We experienced a case of EMH which developed in cranial dura mater after irradiation against massive splenomegaly. As general condition of the patient did not allow us pathological examination, the diagnosis was confirmed by postmortem autopsy.

Clomiphene citrate (CC) is the first-line medication for inducing ovulation in women with polycystic ovary syndrome (PCOS). However, approximately 20% of patients with PCOS are resistant to CC. This study aims to identify reliable baseline predictors of CC resistance in infertile women with PCOS.

A post-hoc analysis of a large, multicenter randomized controlled trial (PCOSAct trial) conducted in China. The current analysis comprised the 471 participants who were randomized to the active CC arm and completed the requisite follow-up. To identify potential candidate variables, we employed multivariable logistic and LASSO regression analyses. Within the framework of a multivariable logistic regression model, we also estimated the independent associations between the identified candidate variables and resistance to CC. Additionally, we plotted the Receiver Operating Characteristic (ROC) curve and utilized the DeLong method to compare the statistical differences in the area under the curve (AUC). Finally, we constructed a restricted cubic spline (RCS) logistic regression model to illustrate the dose-response relationship between continuous predictor variables and CC resistance.

CC resistance was identified in 32 (6.8%) participants. Body Mass Index (BMI), Total Testosterone (TT), and Anti-Müllerian Hormone (AMH) were useful predictors of ovarian response to CC. The "T+BMI" dual-factor model demonstrated high discriminative power (AUC = 0.801) and was statistically comparable to the three-factor model including AMH (AUC = 0.818; P = 0.347). TT was the strongest individual predictor (OR = 2.73 per 1-unit), while BMI was the most significant modifiable risk factor (OR = 2.49 per 1-SD).

A simplified "T + BMI" assessment provides comparable prognostic utility without the need for AMH testing. For patients at high risk of CC resistance, we recommend upfront use of aromatase inhibitors or low-dose gonadotropins. This strategy avoids ineffective treatment cycles and enables personalized ovulation induction.

The study was registered on ClinicalTrials.gov under the identification number NCT01573858 on July 6, 2012.

BRCA1 c.181T>G (p.Cys61Gly) is a pathogenic founder genetic variant prevalent in Central and Eastern Europe. The data on its clinicopathological manifestations in Ukrainian patients remain limited.

This study aimed to characterize clinical presentation, tumor biology, and family history in Ukrainian women with BRCA1 c.181T>G variant.

We conducted a single-centre case series of women with primary breast cancer (BC) and/or ovarian cancer (OC) harbouring BRCA1 c.181T>G genetic variant and treated at Lviv Regional Oncology Treatment and Diagnostic Center (Ukraine) between January 2024 and August 2025. Clinical presentation, tumor pathology, biomarker status, family history, treatment, and outcomes were analysed.

Thirteen women aged 29-81 years (median 35 years) were included in this case series. Early-onset BC was recorded in 10 (76.9%) of patients diagnosed before 40 years. BC was the initial malignancy in 12 (92.3%) patients. OC occurred as a first tumor in 1 (7.7%) and as a subsequent cancer in 4 (30.8%) patients. Multiple malignancies were observed in 61.5% of patients, with intervals of 5-21 years between diagnoses. Family history revealed strong clustering of BC and OC across generations, often involving multiple affected relatives, consistent with hereditary breast and ovarian cancer syndrome phenotype. Among cases with known biomarker status (10/13), 2 were HER2-positive, 4 belonged to luminal-like type, and 4 cases represented triple negative BC. Most cases (10/13, 76.9%) were diagnosed at early tumor growth stage (pT1-2). However, more than half of primary tumors (8 of 13; 61.5%) had positive nodal status (pN1-2) reflecting invasive behaviour of cancer cells.

This Ukrainian case series demonstrates that the BRCA1 c.181T>G genetic variant is associated with early-onset breast cancer, variable tumor biology, frequent multiple primary cancers, and strong familial clustering. These observations support the need for expanded genetic testing, targeted surveillance, and corresponding risk reduction strategies tailored to Ukraine's BRCA1 founder pathogenic variant landscape.