Cancer Biol. Ther. [JOURNAL]
Sun
200 papers
Effective treatment of human breast tumors by chimeric CCL2 and CCL8 diphtheria toxin cytotoxic peptides.
Chavez B, Sikirzhytski V, Lim CU … +2 more , Chatzistamou I, Kiaris H
Cancer Biol Ther · 2026 Dec · PMID 42390481 · Publisher ↗
OBJECTIVE: Chemokine receptors play crucial roles in tumor onset and progression, but the high redundancy between ligands and their receptors limits the possibilities to leverage them therapeutically for cancer managemen...
OBJECTIVE: Chemokine receptors play crucial roles in tumor onset and progression, but the high redundancy between ligands and their receptors limits the possibilities to leverage them therapeutically for cancer management. To overcome this limitation, we developed chimeric chemokine peptides in which CCL2 and CCL8 were conjugated to diphtheria toxin (DT) and evaluated their antitumor activity. METHODS: Cytotoxic peptides DTCCL2 and DTCCL8 were produced as recombinant proteins, and their anticancer activity was tested in cultured cells and in tumor-bearing mice. The uptake of the cytotoxic analogs was evaluated before and after therapy in tumor explants . RESULTS: Both analogs were cytotoxic to breast cancer cells in vitro and produced significant anticancer activity in vivo in mice bearing human breast cancer lines and hormone-negative breast cancer patient-derived xenografts (PDXs). In vitro, the peptide conjugates exhibited overlapping uptake profiles, with about 80% of the breast cancer cells being positive for both peptides and about 15%-20% of the cells being negative for either or both of the cytotoxic peptides. In tumor explants cultured ex vivo, simultaneous positivity for DTCCL2 and DTCCL8 increased to >95%, with less than 5% of the cells showing neither DTCCL8 nor DTCCL2 uptake. Treatment of breast cancer-bearing mice with DTCCL8 or DTCCL2 significantly inhibited tumor growth and prolonged survival in the PDX model. CONCLUSION: These results support the feasibility of cytotoxic peptide conjugates for breast cancer management and show that receptor expression profiles in vitro do not accurately forecast tumoral positivity.
mediates m5C methylation to inhibit ferroptosis and promote breast cancer progression.
Li J, Li M, Guo J … +5 more , Li D, Yao Y, Zhang W, Cui C, Fu B
Cancer Biol Ther · 2026 Dec · PMID 42377119 · Full text
BACKGROUND: Due to the heterogeneity of breast cancer (BRCA) and the limited therapeutic efficacy in specific molecular subtypes, identifying new and effective therapeutic targets remains an urgent clinical need. The tra...
BACKGROUND: Due to the heterogeneity of breast cancer (BRCA) and the limited therapeutic efficacy in specific molecular subtypes, identifying new and effective therapeutic targets remains an urgent clinical need. The transcription factor has been shown to play distinct roles in tumorigenesis and progression, but its specific role in BRCA remains unclear. Therefore, this study investigates the effects of on BRCA progression. METHODS: expression in the TCGA and clinical BRCA tissue samples was analyzed. Cell and animal models were established to validate the effects of on BRCA cell proliferation, migration, and tumorigenicity. Molecular experiments were performed to investigate the association between NSUN2 and SALL2 in BRCA and cellular ferroptosis regulation by SALL2. RESULTS: is significantly overexpressed in BRCA tissues and cell lines, knocking down reduces BRCA cell growth, migration, and tumorigenesis and models. The m5C methyltransferase NSUN2, together with the reader protein YBX1, modifies mRNA with m5C, which stabilizes the transcript. then acts as a transcriptional repressor by binding directly to the promoter region of and inhibiting its transcriptional activity. Suppression of activates ferroptotic cell death by lowering the antioxidant defences of GPX4/SLC7A11 and increasing the expression of and . Ferroptosis inhibitors can reverse the growth-inhibiting effects caused by depletion. CONCLUSION: In BRCA, is precisely regulated by m5C RNA methylation modification, further promoting cancer progression by inhibiting cell ferroptosis, suggesting its potential as a prognostic biomarker and a target for therapy.
Targeting the PI3K/AKT pathway in prostate cancer: the role of PTEN deficiency and biomarker-guided therapy.
Staton A, Abel M, Figg WD
Cancer Biol Ther · 2026 Dec · PMID 42359636 · Full text
Loss of the tumor suppressor gene is a common molecular feature in advanced prostate cancer and is associated with activation of the PI3K/AKT signaling pathway, which controls cell growth and survival. Despite major adv...
Loss of the tumor suppressor gene is a common molecular feature in advanced prostate cancer and is associated with activation of the PI3K/AKT signaling pathway, which controls cell growth and survival. Despite major advances in the treatment of metastatic castration-sensitive prostate cancer (mCSPC), patients with PTEN-deficient tumors represent an aggressive subgroup with poorer clinical outcomes and limited targeted therapeutic options. Capivasertib is a selective oral AKT inhibitor designed to suppress downstream signaling from PI3K pathway activation. We highlight the recent results from the Phase III CAPItello-281 trial (NCT04493853) demonstrating that the addition of capivasertib to abiraterone acetate and androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival in patients with -deficient mCSPC, leading to the FDA-approval of this regimen. Notable adverse events in the cabavisertib arm included hyperglycemia, diarrhea, and rash. CAPItello-281 addresses a significant unmet need for -deficient mCSPC, suggesting AKT inhibition as a potential new targeted treatment strategy for a sub-population with poor prognosis.
ABHD17C regulates the efficacy of lenvatinib in suppressing hepatocellular carcinoma.
Wang L, Wang J, Ma X … +8 more , Huang J, Sun Y, Shi C, Zhang J, Li P, Xu H, Lin H, Wang W
Cancer Biol Ther · 2026 Dec · PMID 42358063 · Full text
INTRODUCTION: Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC), but its clinical efficacy is limited by drug resistance. ABHD17C, a depalmitoylation enzyme involved in HCC progression, has not been i...
INTRODUCTION: Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC), but its clinical efficacy is limited by drug resistance. ABHD17C, a depalmitoylation enzyme involved in HCC progression, has not been investigated in lenvatinib response. This study aimed to determine whether ABHD17C regulates the anti-tumor efficacy of lenvatinib in HCC. METHODS: Published single-cell RNA sequencing (scRNA-seq) data were analyzed to characterize ABHD17C expression in the HCC tumor microenvironment. Functional assays were performed in HCC cell lines to evaluate the effects of lenvatinib and ABHD17C modulation. The findings were validated using HCC xenograft mouse models and patient-derived tumor organoids. RESULTS: scRNA-seq analysis showed that ABHD17C is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T cell infiltration, increased T cell exhaustion, and abnormal intercellular communication. In vitro, lenvatinib inhibited proliferation, migration, and invasion while inducing apoptosis and cell cycle arrest in HCC cells. These effects were significantly attenuated by ABHD17C overexpression but enhanced by ABHD17C depletion. In vivo, ABHD17C-overexpressing xenografts were less responsive to lenvatinib, exhibiting increased tumor growth and reduced apoptosis. Similarly, in patient-derived organoids, ABHD17C overexpression diminished lenvatinib efficacy. Notably, lenvatinib reduced ABHD17C expression in organoids, suggesting potential feedback regulation. CONCLUSION: ABHD17C promotes an immunosuppressive tumor microenvironment and attenuates the anti-tumor effects of lenvatinib in HCC. Targeting ABHD17C may represent a potential strategy to enhance lenvatinib sensitivity and improve therapeutic outcomes.
Advances in SEC61G research: from ER translocon subunit to emerging pan-cancer oncogenic roles.
Man YN, He ML
Cancer Biol Ther · 2026 Dec · PMID 42345355 · Full text
SEC61G, the subunit of the Sec61 translocon, has long been regarded as a passenger co-amplification target of EGFR on chromosome 7p11.2. Recent studies have revealed its independent oncogenic functions across multiple c...
SEC61G, the subunit of the Sec61 translocon, has long been regarded as a passenger co-amplification target of EGFR on chromosome 7p11.2. Recent studies have revealed its independent oncogenic functions across multiple cancers. This review proposes a mechanism-based classification of SEC61G oncogenic activities: (1) immune checkpoint regulation via canonical translocation; (2) aberrant calcium signaling; and (3) non-canonical mechanisms independent of channel functions. We further delineate the pan-cancer expression and CRISPR-Cas9 dependency landscape, highlighting a dual "high expression, high dependency" profile in cervical squamous cell carcinoma. We distinguish current pore-targeting Sec61 inhibitors from subunit-specific strategies and propose future directions including PROTAC degraders and PPI inhibitors. Our review identifies SEC61G as a pan‑cancer prognostic biomarker and immunotherapy response predictor, with mechanistic evidence supporting its driver roles in glioblastoma, non‑small cell lung cancer, and colorectal cancer, whereas associations in other cancers remain correlative and require further validation.
Efficacy and safety profiles of CDK4/6 inhibitor in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) from the high-altitude low-altitude regions: a multi-center retrospective study.
Tan Y, Ye Y, Zhao W … +4 more , Jiang H, Wang J, Zhao J, Ma F
Cancer Biol Ther · 2026 Dec · PMID 42337391 · Full text
BACKGROUND: CDK4/6 inhibitors (CDK4/6i) represent the standard treatment for HR+/HER2- ABC. The study assessed the efficacy and safety profiles of CDK4/6i from first-line (1 L) to third-line (3 L) in patients with HR+/HE...
BACKGROUND: CDK4/6 inhibitors (CDK4/6i) represent the standard treatment for HR+/HER2- ABC. The study assessed the efficacy and safety profiles of CDK4/6i from first-line (1 L) to third-line (3 L) in patients with HR+/HER2- ABC from high-altitude low-altitude regions. MATERIALS: HR+/HER2- ABC patients who received CDK4/6i were enrolled from four cancer centers in China. RESULTS: A total of 350 patients were eligible for the study, involving 268 from the low-altitude group and 82 from the high-altitude group. In the 1 L, objective response rate (ORR, 23.7% 5.3%, = 0.01), clinical benefit rate (CBR, 88.1% 57.9%, < 0.0001), and median progression-free survival (PFS, 42.1 months 15.2 months, = 0.001) in the low-altitude group were superior to those in the high-altitude group. In the second-line treatment, CBR in the low-altitude group was higher (87.5% 48.0%, = 5.3E-4). The ORR (20.8% 4.0%, = 0.08) and PFS (15.8 months 8.2 months, = 0.11) were not significantly different. In the 3 L settings, no significance was observed in PFS (5.2 months 5.8 months, = 0.45), ORR (16.5% 21.1%, = 0.74), and CBR (47.1% 47.4%, = 1). The incidence of anemia (43.9% 28.3%, = 0.01), ≥grade 3 anemia (9.8% 1.9%, = 3.10E-03), ≥grade 3 thrombocytopenia (9.8% 1.9%, = 3.10E-03), ≥grade 3 ALT (6.1% 0.4%, = 3.10E-03) and AST (7.3% 1.9%, = 0.02) dysfunction occurred more frequently in the high-altitude group. CONCLUSION: Patients with HR+/HER2- ABC in the high-altitude region experienced inferior survival outcomes and individualized tolerability to CDK4/6i, which may inform scientific research and the management of CDK4/6i in Chinese patients with HR+/HER2- ABC.
The dual role of leukotrienes in the tumor microenvironment: balancing pro-tumorigenic and anti-tumor immunity.
Thake A, Caruso M, Fernandez-Bussy S … +1 more , Sacco K
Cancer Biol Ther · 2026 Dec · PMID 42335104 · Full text
BACKGROUND: Leukotrienes are bioactive lipid mediators produced via the 5-lipoxygenase (5-LO) pathway and are essential for inflammatory signaling in the tumor microenvironment (TME), playing roles in angiogenesis, immun...
BACKGROUND: Leukotrienes are bioactive lipid mediators produced via the 5-lipoxygenase (5-LO) pathway and are essential for inflammatory signaling in the tumor microenvironment (TME), playing roles in angiogenesis, immune modulation and metastatic progression. OBJECTIVE: This review evaluates the role of leukotriene signaling in cancer progression and highlights biomarker-guided therapeutic strategies targeting these pathways in the TME. METHODS: A narrative review of preclinical, clinical, and epidemiological studies was performed, with prespecified inclusion criteria and prioritization of recent evidence. RESULTS: Leukotriene-mediated signaling correlates with biomarkers such as CysLT1 receptor expression, -catenin activation, and HIF-1α signaling. In preclinical models, pharmacological agents including montelukast, zileuton, and FLAP antagonists suppress tumor growth, and restore apoptotic signaling; current clinical evidence remains largely observational and pharmacoepidemiologic. CONCLUSION: Targeting this pathway represents a promising avenue in oncology, with potential to enhance precision medicine through biomarker-guided patient stratification. Further clinical validation is warranted to translate these findings into therapeutic benefit.
CD69 blockade restores the bone marrow niche and delays leukemogenesis in a mouse model of -driven chronic myelomonocytic leukemia.
Li Y, Jiang X, Gu Y … +9 more , Zha X, Wu J, Wu X, Qi C, Chen S, Li Y, Jin Z, Xia C, Xu L
Cancer Biol Ther · 2026 Dec · PMID 42330053 · Full text
BACKGROUND: A subset of patients with chronic myelomonocytic leukemia (CMML) carries mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. Howev...
BACKGROUND: A subset of patients with chronic myelomonocytic leukemia (CMML) carries mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. However, the effects of mutations on the bone marrow microenvironment (BME) remain unclear. METHODS: We used a CMML mouse model driven by a single allele mutation to investigate alterations in the BME and the potential role of CD69 in immune suppression. -mutated CMML mice were treated with an anti-CD69 monoclonal antibody. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing were performed to evaluate treatment-related changes. RESULTS: -mutated CMML mice showed increased infiltration of regulatory T (Treg) cells and CD69 T cells in the BME, whereas CD69 expression on peripheral blood T cells remained lower than that on bone marrow T cells. Anti-CD69 monoclonal antibody treatment was associated with reduced generation of granulocyte-macrophage progenitor cells, prolonged survival, and decreased Treg accumulation in the BME. CONCLUSION: Our findings suggest that CD69 may serve as a biomarker of BME immunological dysfunction in CMML.
KIF18A inhibitor prevents chromosomally unstable osteosarcoma growth by activating spindle assembly checkpoint.
Yan Q, Zhang Y, Wang P … +6 more , Fu Y, Ke C, Han S, Xing J, Li H, Zhang K
Cancer Biol Ther · 2026 Dec · PMID 42328720 · Full text
BACKGROUND: Osteosarcoma survival rates have not improved significantly in decades, as complex gene mutations and intratumoral heterogeneity hinder new therapy development. To exploit the widespread chromosomal instabili...
BACKGROUND: Osteosarcoma survival rates have not improved significantly in decades, as complex gene mutations and intratumoral heterogeneity hinder new therapy development. To exploit the widespread chromosomal instability in osteosarcoma, we investigated targeting the essential mitotic motor protein KIF18A. MATERIALS: Two whole-genome-doubling clones derived from the near-diploid SJSA1 osteosarcoma cell line were used to evaluate sensitivity to KIF18A knockout or pharmacological inhibition. The traditional osteosarcoma cell lines U2OS and MG63 were included in the study of the KIF18A inhibitor at both the cellular and xenograft (nude mice) levels. RESULTS: Depletion of KIF18A significantly reduced cell viability, survival, and proliferation in the SPT cell, but not in the parental SJSA1 cell. Loss of KIF18A expression led to aberrant spindle assembly and mitotic delay through the activation of spindle assembly checkpoint (SAC) signaling. Therefore, the deficiency of SAC rescued the SPT cell growth. We then tested one of the latest KIF18A inhibitors, AM-1882, in SPT, U2OS, and MG63 cells. It showed potent anti-cancer activity and disruption of spindle assembly activity, just like the KIF18A knockout. In the mouse xenograft model, AM-1882 also apparently prevented tumor growth and, notably, did not show any toxicity when compared with chemotherapeutic drugs. CONCLUSION: Overall, our study demonstrated that KIF18A is a promising therapeutic target in osteosarcoma. The novel inhibitor AM-1882 offers exceptional anti-tumor efficacy paired with a favorable, low-toxicity safety profile.
ADAR1-circRAB5A-BIP axis governs radiotherapy resistance in colorectal cancer through coordinating protective autophagy and apoptosis.
Chen W, Zhang X, Zhao Z … +3 more , Xin W, Li J, Che X
Cancer Biol Ther · 2026 Dec · PMID 42324593 · Full text
BACKGROUND: Colorectal cancer (CRC) ranks among the most prevalent malignancies globally, and radiotherapy remains a critical treatment modality. However, its efficacy is frequently compromised by acquired radioresistanc...
BACKGROUND: Colorectal cancer (CRC) ranks among the most prevalent malignancies globally, and radiotherapy remains a critical treatment modality. However, its efficacy is frequently compromised by acquired radioresistance. The endoplasmic reticulum chaperone protein BIP plays a pivotal role in regulating radioresistance by coordinating the balance between protective autophagy and apoptosis, though the regulatory roles of circular RNAs (circRNAs) in this process remain poorly understood. MATERIALS: Differentially expressed circRAB5A (hsa-circ-0123297) was identified from the GSE186940 dataset. Its expression was validated in radioresistant CRC clinical samples and cell lines. Mechanistic investigations involved ADAR1 binding assays, circRAB5A gain/loss-of-function studies, autophagy-apoptosis profiling, ubiquitination analysis, TRIM21-mediated degradation assays, and xenograft models. RESULTS & CONCLUSION: CircRAB5A was significantly downregulated in radioresistant CRC clinical samples and cell lines. This downregulation was driven by ADAR1, which suppressed circRAB5A biogenesis by binding to Alu Jo/Jr elements. Functional assays showed circRAB5A depletion conferred radioresistance in CRC cells by promoting protective autophagy and inhibiting apoptosis. Mechanistically, circRAB5A destabilized BIP by enhancing TRIM21-mediated ubiquitination. The circRAB5A/BIP axis further modulates the autophagy-apoptosis balance through the p-Akt/Beclin1 signaling pathway, thereby influencing radiosensitivity. xenograft experiments demonstrated that stable knockdown of circRAB5A attenuated the anti-tumor effects of radiation, whereas knockdown of BIP sensitized CRC cells to radiotherapy even at low doses. Collectively, the ADAR1/circRAB5A/BIP molecular circuitry governs CRC radioresistance by regulating the autophagy-apoptosis balance. Our findings highlight that low circRAB5A expression may serve as a potential biomarker for radioresistance, and that targeting this axis, particularly BIP, represents a promising strategy for overcoming radioresistance in CRC.
Opsonization and timing as key determinants of MBTA immunotherapy efficacy in pancreatic adenocarcinoma and recurrence treatment.
Frejlachova A, Lencova R, Uher O … +8 more , Vanova KH, Martinkova K, Cizkova M, Vetvicka D, Langhansova H, Kopecky J, Pacak K, Zenka J
Cancer Biol Ther · 2026 Dec · PMID 42318705 · Full text
BACKGROUND: Pancreatic adenocarcinoma is a highly aggressive cancer with very limited treatment options. This study aimed to optimize the efficacy of a previously developed tumor immunotherapy for the treatment of this d...
BACKGROUND: Pancreatic adenocarcinoma is a highly aggressive cancer with very limited treatment options. This study aimed to optimize the efficacy of a previously developed tumor immunotherapy for the treatment of this disease and its recurrences. METHODS: Mouse models of pancreatic and colon adenocarcinoma were established using Panc02 and MC38 cells, respectively. Tumors were treated by intratumoral administration of MBTA, a formulation containing resiquimod, poly(I:C), LTA, anti-CD40 antibody, and mannan-BAM (a phagocytosis-stimulating mannan anchored to the tumor cell membrane via a biocompatible membrane anchor, BAM). Multiple variants of the therapy were tested, differing in composition and timing, including treatment of recurrences. RESULTS: Intratumoral MBTA immunotherapy administered using an optimized 5 × 2 schedule resulted in an 87.5% survival rate in mice bearing subcutaneous Panc02 tumors. MBTA immunotherapy also effectively treated spontaneous local Panc02 recurrences that developed in a small subset of mice. High efficacy of MBTA was further confirmed in a murine model of colon adenocarcinoma. CONCLUSION: These findings suggest that MBTA is a promising therapeutic approach for primary and recurrent pancreatic adenocarcinoma, with potential for broader clinical application.
ULK1's role in cancer progression and its emerging therapeutic potential.
Webb JD, Shepherd TG
Cancer Biol Ther · 2026 Dec · PMID 42308349 · Publisher ↗
Macroautophagy (autophagy) enables cellular stress adaptation by degrading damaged components; ULK1, a serine/threonine kinase, initiates this process in response to nutrient and energy cues. While autophagy is well stud...
Macroautophagy (autophagy) enables cellular stress adaptation by degrading damaged components; ULK1, a serine/threonine kinase, initiates this process in response to nutrient and energy cues. While autophagy is well studied, few investigations have directly tested ULK1 in cancer progression. Emerging functional data across numerous cancers indicate that ULK1 can promote or restrain malignant behavior through both autophagy-dependent and autophagy-independent mechanisms, modulating mitochondrial quality, anoikis escape, invasion, therapy adaptation, and immune visibility. Pharmacology has advanced from early ULK1/2 inhibitors to structure-guided and machine learning-derived inhibitors with improved potency and selectivity. The first clinical agent, DCC-3116, demonstrates on-target engagement with acceptable tolerability and is being evaluated in combinations where therapy induces autophagy. Here, we review ULK1 as a regulator of cancer progression, synthesizing pan-cancer clinical and functional evidence alongside the evolving pharmacology of ULK1 modulation to define the settings in which its targeted inhibition may be most effectively translated.
Retinol dehydrogenase 11 promotes prostate cancer progression through upregulation of tropomyosin receptor kinase A.
Wang S, Zhang S, Xin Z … +7 more , Lei Z, Xiong J, Shi Y, Yang L, Gao Q, Le K, Zhang B
Cancer Biol Ther · 2026 Dec · PMID 42304957 · Publisher ↗
OBJECTIVE: To clarify the clinical significance and biological function of retinol dehydrogenase-11 (RDH11) in prostate cancer (PCa) and to elucidate the downstream signaling mechanism through which it drives tumor progr...
OBJECTIVE: To clarify the clinical significance and biological function of retinol dehydrogenase-11 (RDH11) in prostate cancer (PCa) and to elucidate the downstream signaling mechanism through which it drives tumor progression. METHODS: Public and in-house transcriptomic data were mined to compare RDH11 levels between PCa and matched normal tissues. RDH11 was stably silenced (shRDH11) or over-expressed (oeRDH11) in PC-3, DU145, and LNCaP cells; cell proliferation, migration, and invasion were quantified with CCK-8 and Transwell assays. RNA-seq and gene set enrichment analysis (GSEA) were performed to screen downstream targets and pathways. Rescue experiments in vitro and in vivo were used to confirm the mechanism. RESULTS: RDH11 levels were markedly elevated in human PCa tissues and cell lines. Silencing RDH11 hindered PCa cell proliferation, migration, and invasion, whereas its overexpression had the opposite effects. Mechanistically, we identified the tropomyosin receptor kinase (TRKA) and STAT3 signaling pathway as the downstream gene and pathway of RDH11. Rescue assays using PC3, DU145, and LNCaP cells demonstrated that RDH11 facilitated PCa progression by upregulation of TRKA and the activation of STAT3 signaling. studies further confirmed that RDH11 overexpression enhanced prostate tumor growth, whereas TRKA knockdown counteracted the oncogenic effects of RDH11. CONCLUSION: RDH11 promotes the development of PCa through the upregulation of TRKA and activation of the STAT3 signaling pathway.
STARD10 promotes progression of HER2+ breast cancer and intracellular lipid metabolism via the cAMP/PKA/CREB1 signaling axis.
Liu S, Gao J, Niu Y … +7 more , Dong X, Zhang Z, Teng X, Li Z, Zhang S, Meng Y, Gao MQ
Cancer Biol Ther · 2026 Dec · PMID 42296148 · Full text
BACKGROUND: Although targeted therapies have improved clinical outcomes, HER2+ breast cancer remains a significant clinical challenge due to its aggressive behavior and unfavorable prognosis. Emerging evidence indicates...
BACKGROUND: Although targeted therapies have improved clinical outcomes, HER2+ breast cancer remains a significant clinical challenge due to its aggressive behavior and unfavorable prognosis. Emerging evidence indicates that dysregulated lipid metabolism plays a critical role in tumorigenesis and metastasis, suggesting that targeting lipid metabolism may represent a promising therapeutic strategy. STARD10, a lipid transport protein, plays a pivotal role in regulating lipid metabolism. However, its function in mediating lipid metabolism and tumor progression in HER2+ breast cancer remains unclear. METHODS: The expression level and prognostic relevance of STARD10 in HER2+ breast cancer were analyzed using public databases and clinical cohorts. CCK-8, EdU, colony formation, transwell, LD540, and Nile Red staining assays were performed in SKBR3 and HCC1954 cells. Subcutaneous implantation and tail vein injection were performed to evaluate the effects of STARD10 overexpression on tumor growth and lung metastasis in vivo. The mechanism was validated by RNA-seq and Western blotting. RESULTS: STARD10 expression was upregulated in HER2+ breast cancer tissues and was significantly correlated with poor prognosis. Functionally, STARD10 overexpression enhanced HER2+ breast cancer cell proliferation, migration, invasion, and lipid droplets accumulation. Moreover, STARD10 overexpression markedly accelerated tumor growth and lung metastasis in vivo. Mechanistically, STARD10 was found to drive malignant phenotypes via activation of the cAMP/PKA/CREB1 signaling axis. CONCLUSION: STARD10 promotes malignant progression of HER2+ breast cancer and lipid droplets accumulation by activating the cAMP/PKA/CREB1 pathway. These findings suggest that STARD10 and the cAMP/PKA/CREB1 signaling axis as potential therapeutic targets for the treatment and prevention of HER2+ breast cancer.
The tumor microenvironment in triple negative breast cancer and a strategy to improve responses to immunotherapy using cryoablation and immunostimulants.
Illindala R, Yang Y, Mandt T … +3 more , Webster N, Steinmetz N, Newton I
Cancer Biol Ther · 2026 Dec · PMID 42247481 · Full text
One in eight women will develop breast cancer (BC) over their lifetime. Triple-negative breast cancer (TNBC) accounts for up to 20% of BC cases and has fewer treatment options, greater metastatic potential, a higher risk...
One in eight women will develop breast cancer (BC) over their lifetime. Triple-negative breast cancer (TNBC) accounts for up to 20% of BC cases and has fewer treatment options, greater metastatic potential, a higher risk of recurrence, and a poorer prognosis compared to other BC subtypes. Compared to hormone receptor-positive BCs, TNBC has more tumor-infiltrating lymphocytes, a higher tumor mutational burden, and greater programmed death ligand-1 (PD-L1) expression. While these features suggest greater immunogenicity, the balance of the complex TNBC tumor microenvironment (TME) is immunosuppressive. The TME leads to modest and variable effects of immune checkpoint inhibitors (ICI) for TNBC. This review explores the dysfunctional immunological state of TNBC and proposes a multi-modal strategy integrating cryoablation as a source of tumor-associated antigens (TAAs) and immunostimulatory agents to reprogram antitumor immunity. It specifically explores the strategy of combining ICI and immunostimulants with cryoablation as a source of TAAs.
Neoplastic CD3⁺ B cells remodel the DLBCL tumor microenvironment via single-cell and spatial transcriptomics.
Lang M, Feng Y, Zhou L … +10 more , Li B, Li W, Zhao J, Chen K, Li L, Qiu L, Qian Z, Zhou S, Zhang H, Chu Z
Cancer Biol Ther · 2026 Dec · PMID 42247321 · Full text
INTRODUCTION: This study constructs a high-resolution multi-omics map of Diffuse Large B-Cell Lymphoma (DLBCL) by integrating single-cell, single-nucleus, and spatial transcriptomics. METHODS: We identified a previously...
INTRODUCTION: This study constructs a high-resolution multi-omics map of Diffuse Large B-Cell Lymphoma (DLBCL) by integrating single-cell, single-nucleus, and spatial transcriptomics. METHODS: We identified a previously unrecognized, recurrent subset of malignant B cells that unexpectedly express CD3, a protein typically found only on T cells. This unusual CD3⁺ B cell population appears to be driven by a specific genetic circuit involving five key regulatory genes: BCLAF1, CHURC1, FLI1, NFATC2, and ELF2. RESULT: Spatial and functional analyses revealed that these cells are associated with macrophage enrichment and M2 polarization, potentially involving TGF- signaling and contributing to an immunosuppressive tumor microenvironment. Clinically, the abundance of CD3⁺ B cells was associated with advanced disease stage, poor treatment response, and reduced survival. CONCLUSION: Our findings support the presence of a CD3⁺ B cell subset with T cell-like features that is associated with tumor microenvironment remodeling and adverse clinical outcomes, highlighting molecular determinants like FLI1 and the TGF- axis as potential therapeutic targets.
Leveraging the bacteria for enhanced cancer immunotherapy: from a perspective of synthetic biology.
Liu X, Zhang H, Du R … +3 more , Liu Z, Ren Y, Yang X
Cancer Biol Ther · 2026 Dec · PMID 42240055 · Full text
In recent years, synthetic biology has been widely applied to engineer and program cellular behaviors. Using this approach, bacteria can be designed to express immunotherapeutic agents, improve tumor targeting, and deliv...
In recent years, synthetic biology has been widely applied to engineer and program cellular behaviors. Using this approach, bacteria can be designed to express immunotherapeutic agents, improve tumor targeting, and deliver therapeutic payloads directly to tumor sites. To further improve efficacy, strategies such as hypoxia-responsive promoters, bacterial swarming, and extracellular vesicles (EVs) have been investigated, along with the synergistic effects of combining bacterial therapy with other treatments (e.g., photodynamic therapy, chemotherapy, immune checkpoint inhibitors). This review summarizes recent advances in synthetic biology for bacteria-based cancer immunotherapies, focusing on how bacterial agents activate the immune system and the engineering strategies used to achieve tumor targeting.
fusion partners dictate oncogenic potential in undifferentiated spindle cell sarcomas.
Gui Q, Zhang Y, Yang M … +10 more , Liang R, Huang M, Yang X, Chen N, Chen X, Wu M, Chen H, Meng L, Xiao S, Tao M
Cancer Biol Ther · 2026 Dec · PMID 42240026 · Full text
BACKGROUND: Spindle cell tumors with rearrangements exhibit variable clinical behaviors, ranging from benign to highly aggressive malignancies. The underlying heterogeneity is suspected to be associated with distinct fu...
BACKGROUND: Spindle cell tumors with rearrangements exhibit variable clinical behaviors, ranging from benign to highly aggressive malignancies. The underlying heterogeneity is suspected to be associated with distinct fusion partner genes. Understanding the impact of these fusion partners on oncogenic potential is crucial for precision therapy. METHODS: We report a case of a spindle cell tumor harboring an fusion, which initially responded to anti-RET therapy but relapsed due to an fusion. Isogenic cell lines expressing MYH10::RET and CCDC6::RET were established. Functional assays, including cell proliferation, migration, invasion, and kinase activity assays, were performed. Genomic profiling was conducted using targeted DNA and RNA NGS and FISH. RESULTS: MYH10::RET-expressing cells showed significantly higher proliferation, migration, and invasion compared to CCDC6::RET-expressing cells. MYH10::RET exhibited approximately three-fold higher kinase activity. The patient's disease was managed through sequential targeted therapies, including combination therapy with third-generation inhibitors targeting RET and NTRK. CONCLUSION: Our findings suggest that distinct fusion partners significantly contribute to the clinical heterogeneity of -rearranged spindle cell tumors, likely through differential kinase activity. Continuous genomic monitoring is essential for identifying resistance mechanisms and guiding precision therapy. Future studies should explore the impact of different fusion partners on tumor behavior and therapeutic response.
TFPI2 in tumor metastasis: a double-edged sword with clinical implications.
Guo Z, Luo Y, Wen J … +7 more , Jiang Y, Kuang Q, Ma Q, Zheng C, Li X, You F, Fu X
Cancer Biol Ther · 2026 Dec · PMID 42216563 · Full text
Tissue factor pathway inhibitor 2 (TFPI2), a serine protease inhibitor, plays a multifaceted role in tumor metastasis. Traditionally viewed as a metastasis suppressor, it inhibits extracellular matrix (ECM) remodeling, e...
Tissue factor pathway inhibitor 2 (TFPI2), a serine protease inhibitor, plays a multifaceted role in tumor metastasis. Traditionally viewed as a metastasis suppressor, it inhibits extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition, and angiogenesis. However, emerging evidence indicates that TFPI2 promotes tumor progression in glioblastoma, melanoma, and other cancers by fostering an immunosuppressive tumor microenvironment, mediating pathological ECM remodeling, and enhancing angiogenesis and hematogenous dissemination. Notably, even within the same metastatic cascade, TFPI2 exhibits divergent expression patterns and context-dependent opposing functions, acting either as a metastasis suppressor or promoter. This review summarizes its context-dependent regulatory mechanisms, investigates the underlying basis from structural duality, microenvironmental heterogeneity, and receptor differences, and evaluates its potential as a therapeutic target. Future research should elucidate spatiotemporal microenvironmental dynamics to support early screening and precise intervention.
Suppression of LncRNA AC008406.3 sensitizes breast cancer cells to docetaxel via triggering cuproptosis.
Liu C, Liu S, Lu Z … +5 more , Cao X, Tong X, Sun I, Hao J, Zhang L
Cancer Biol Ther · 2026 Dec · PMID 42189063 · Full text
BACKGROUND: Docetaxel (DTX) is one of the commonly used chemotherapeutic agents for breast cancer. Cuproptosis, a newly defined form of cell death, significantly influences tumor progression. This study aims to identify...
BACKGROUND: Docetaxel (DTX) is one of the commonly used chemotherapeutic agents for breast cancer. Cuproptosis, a newly defined form of cell death, significantly influences tumor progression. This study aims to identify cuproptosis-related long non-coding RNAs (lncRNAs) involved in regulating the sensitivity of breast cancer to DTX. MATERIALS: Cuproptosis-related prognostic lncRNAs in breast cancer were identified through integrated co-expression, differential expression, and prognostic analyses based on the TCGA-BRCA cohort. The role of the identified lncRNA AC008406.3 in regulating cuproptosis in breast cancer cells was experimentally verified. The impact of DTX on the induction of cuproptosis was investigated, and rescue experiments were conducted to validate the involvement of AC008406.3 in modulating breast cancer sensitivity to DTX. RESULTS: AC008406.3 was identified as a potential cuproptosis-related prognostic lncRNA in breast cancer, exhibiting high expression in breast cancer samples, which was associated with unfavorable prognostic outcomes. Knockdown of AC008406.3 specifically induced cuproptosis in breast cancer cells, as evidenced by increased intracellular copper levels and downregulation of lipoylated proteins and Fe-S cluster proteins, thereby suppressing cell proliferation, invasion, and migration; conversely, AC008406.3 overexpression elicited opposite phenotypic changes. Notably, DTX induced the occurrence of cuproptosis in breast cancer, whereas AC008406.3 suppressed this process, thereby diminishing DTX efficacy. However, AC008406.3 knockdown synergistically enhanced the anti-tumor efficacy of DTX in inhibiting breast cancer growth. CONCLUSION: AC008406.3 reduces the sensitivity of breast cancer to DTX by suppressing cuproptosis. Targeting AC008406.3 may represent a potential strategy to sensitize breast cancer cells to DTX.
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