搜索结果：Oncogene

Growing evidence indicates that lactate and long non-coding RNAs (lincRNAs) exert a crucial influence on tumor development. This study aimed to investigate lactate-induced histone lactylation promotes the roles of lincRNA in lung cancer progression by enhancing proliferation and PD-L1-mediated inhibition of T cell antitumor function. Results showed that both linc00824 and lactate levels were elevated in NSCLC tissues compared to adjacent controls. Lactate upregulated linc00824 expression by regulating histone H3K18 lactylation. Functioning as an oncogene, linc00824 promoted NSCLC cell proliferation and migration. Furthermore, linc00824 upregulated PD-L1 expression through targeting miR-4483 in H1975 cells, thereby suppressing CD8+ T cell activation. MiR-4483 inhibited lung cancer cell proliferation and exhibited synergistic antitumor effects with envafolimab. In summary, lactate-induced histone lactylation drives linc00824 upregulation, facilitating lung cancer progression by enhancing tumor cell proliferation and suppressing T cell antitumor function via regulating miR-4483/PD-L1. We identified an antitumor strategy for lung cancer by using miR-4483.

To assess immunohistochemically the presence of c-Myc both qualitatively and quantitatively in odontogenic cysts and tumours and to correlate the results with biological behaviour of these lesions. Formalin-fixed, paraffin-embedded blocks of odontogenic cysts and tumours were retrieved from institutional archives. The study sample size was 45 (n = 45), which included 10 cases of odontogenic keratocyst cyst (n = 10), five cases of radicular cyst (n = 5), five cases of dentigerous cyst (n = 5), and 10 cases of solid ameloblastoma of which five cases are follicular (n = 5) and five cases are plexiform (n = 5), 10 cases of Adenomatoid odontogenic tumour (n = 10) and five cases of unicystic ameloblastoma (n = 5). Sections were taken and stained immunohistochemically using c-Myc and evaluated both for quantitative and qualitative analysis. In the current study, the mean number of c-Myc positive cells in the odontogenic tumours was highest in solid Ameloblastoma (78.6 ± 11.59), followed by Adenomatoid odontogenic tumor (AOT) (75.30 ± 39.853) and least in unicystic ameloblastoma (56.6 ± 20.53). Among odontogenic cysts, the mean number of c-Myc positive cells was higher in Odontogenic keratocyst (OKC) (73.2 ± 17.937) compared to dentigerous cyst (28.0 ± 27.9) and radicular cysts (31.0 ± 31.7). The staining intensity varied in odontogenic cysts and tumours. The results and observations of the present study show that c-Myc plays a role in the aggressive biological behaviour of odontogenic lesions like ameloblastoma and OKC. So, it can be used as a proliferative marker. However, additional immunohistochemical and DNA assays are to be carried to determine the role of c-Myc oncogene and to know if any mutations may play a role in the pathogenesis of these odontogenic lesions.

Alternative polyadenylation (APA) generates mRNA isoforms with distinct 3' untranslated regions (3'UTRs), thereby influencing transcript stability and translation. In cancer, 3'UTR shortening can activate oncogenes by escaping microRNA (miRNA)-mediated repression, but its role in hepatocellular carcinoma (HCC) remains poorly defined. Here, we profiled mRNA length alterations in multistage human HCC transcriptome datasets and investigated their functional consequences. Approximately 77% of mRNAs with altered length exhibited 3'UTR shortening. Glypican-3 (GPC3) was the most prominently upregulated shortened transcript, and high GPC3 expression was associated with poor prognosis in HCC. GPC3 knockdown reduced proliferation and induced apoptosis, whereas GPC3 overexpression promoted cell growth. Among APA regulators, Cleavage Stimulation Factor 2 (CSTF2) was upregulated in HCC, correlated positively with GPC3 expression, and predicted adverse clinical outcomes. Modulation of CSTF2 expression altered GPC3 3'UTR length, with CSTF2 overexpression promoting GPC3 3'UTR shortening, increasing GPC3 protein expression, enhancing proliferation, and suppressing apoptosis. Further analysis revealed that GPC3 3'UTR shortening removed binding sites for miR-96-5p and miR-140-5p, relieving miRNA-mediated translational repression. These findings identify CSTF2-driven APA as a mechanism of oncogenic GPC3 activation in HCC and suggest the CSTF2-GPC3 axis as a potential therapeutic target. Liver cancer is one of the leading causes of cancer-related death worldwide. Glypican-3 (GPC3) is often highly increased in liver cancer and is being studied as a marker and treatment target, but the reason for its increase is not fully understood. In this study, we analyzed patient datasets, liver cancer cells, and tumor samples to investigate how GPC3 is controlled. We found that liver cancer cells often produce a shortened form of GPC3 RNA. This shorter RNA form avoids regulation by small RNA molecules that normally help keep GPC3 levels low. We also identified CSTF2 as an important factor that promotes this shortening process. As a result, GPC3 becomes more stable and more highly expressed, helping cancer cells grow and survive. These findings reveal a new way that liver cancer cells increase GPC3 and may support future strategies to diagnose or treat liver cancer.

It remains elusive how various therapeutic approaches, including radiotherapy, chemoradiotherapy, and immunoradiotherapy, reshape malignant cells and the tumor microenvironments (TMEs) during esophageal squamous cell carcinoma (ESCC) progression. A mouse model of ESCC induced by 4-nitroquinoline-1-oxide was constructed and handled by therapeutic regimens including radiotherapy, chemoradiotherapy and immunoradiotherapy, followed by single-cell and spatial transcriptomics sequencing. Besides, ESCC tumors were collected from patients during surgery after chemoradiotherapy or immunoradiotherapy. Immunohistochemical staining or immunofluorescence was applied to detect markers associated with a certain treatment. By combining single-cell and spatial transcriptomics, we have deciphered the aberrant gene expression program in epithelial cells and the cellular compositions in the ESCC mouse model following different therapeutic interventions, where chemoradiotherapy moderated epithelial cells essentially by circumscribing several oncogenes and limiting their crosstalk with Hbegf + macrophages. When radiotherapy, chemoradiotherapy, and immunoradiotherapy all lessened the immunosuppressive TMEs, including regulatory T cells and Col12a1 + cancer-associated fibroblasts, immunoradiotherapy might regulate immune responses, especially as evidenced by the frequencies of Ccl5 + Cd8 + T cells elevated. Here, we mapped a comprehensive single-cell and spatial transcriptional panorama of therapy-related ESCC in mouse models. Discovering these spatiotemporal clues might have clinical implications in establishing and improving effective therapy based on these molecules for ESCC.

By positioning phase separation between Kirsten rat sarcoma virus oncogene homolog (KRAS) lipidation and membrane signaling, Wang et al. unify distinct aspects of KRAS biology. They show that farnesylation drives cytoplasmic KRAS condensates that promote processing, trafficking, and signaling, establishing condensat formation as a new mechanism for controlling RAS activity.

Although the efficacy of molecular targeted therapies varies across actionable genomic alterations in NSCLC, comparisons within a single real-world cohort remain limited. We conducted a retrospective multi-institutional study of 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy from 2017 to 2023. Patients were classified into the following three genomic groups: EGFR mutations (group A), ALK/ROS1/RET fusion oncogenes (group B), and others, including MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations (group C). Treatment efficacy and safety were compared across the groups. Treatment outcomes differed between the subgroups. Group B demonstrated the highest objective response rate (85.8%) and the longest median real-world progression-free survival (rwPFS; 42.5 mo); median overall survival (OS) was not reached. Group A had intermediate outcomes. Group C exhibited the shortest rwPFS (9.2 mo), poorer OS, and higher rates of treatment discontinuation due to adverse events. Such hierarchical differences were observed in patients with baseline central nervous system metastases and in those receiving first-line treatment. In multivariate analysis, genomic subgroup remained associated with rwPFS and OS, with fusion-driven tumors maintaining superior outcomes irrespective of other factors. This large real-world analysis yielded a hierarchy of therapeutic benefits across actionable genomic alterations in NSCLC. Patients with fusion-driven tumors benefited from targeted therapy, whereas those with EGFR-mutated tumors had intermediate outcomes. Treatment of patients with MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations had limited efficacy and higher toxicity, underscoring the need for improved therapeutic strategies.

Astrocyte-elevated gene-1 (AEG-1), also known as metadherin (MTDH), is a pleiotropic oncogene critically involved in the onset and development of glioblastoma (GBM), other malignant gliomas, and neuroblastoma. Its expression is upregulated under hypoxic conditions and during glucose deprivation, enabling tumor cells to survive severe metabolic stress while sustaining glycolysis. AEG-1 also has emerged as a reliable prognostic and diagnostic biomarker in gliomas, astrocytomas, oligodendrogliomas, and neuroblastomas. High AEG-1 expression correlates with advanced tumor grade, rapid disease progression, metastasis, and poor overall survival, independent of conventional clinical variables. Co-expression of AEG-1 with MDM2 further predicts higher recurrence and reduced survival, highlighting its value in patient stratification and clinical decision-making. Beyond its prognostic relevance, AEG-1 is a promising therapeutic target. Importantly, gene silencing studies demonstrate that AEG-1 knockdown reduces proliferation, promotes apoptosis, and enhances sensitivity to chemotherapeutic agents such as cisplatin, doxorubicin, and temozolomide. Mechanistically, inhibition of AEG-1 disrupts survival pathways including PI3K/Akt, impairs DNA repair, and attenuates immunosuppressive tumor microenvironments. Small-molecule inhibitors, such as DYT-40, synergistically target AEG-1 and NF-κB, reducing tumor growth and invasion in glioblastoma models. Moreover, AEG-1 suppression sensitizes cancer cells to radiotherapy by impairing homologous recombination repair and enhancing DNA damage-induced apoptosis. Collectively, these findings underscore AEG-1 as a central regulator of tumor progression, chemoresistance, and radioresistance, and support its potential as a target for combinatorial therapeutic strategies to improve outcomes in aggressive brain and pediatric tumors.

Forward genetics screens are routinely employed to perturb thousands of genetic elements in a pooled fashion with the goal of producing large-scale genotype-to-phenotype maps. While often carried out in cell culture systems, accumulating evidence supports that in vivo screens have the power to unveil new biology that cannot be recapitulated in vitro. However, the widespread application of this approach has been limited by two major challenges: a predominant focus on loss-of-function perturbations rather than gene activation and the significant technical hurdles of delivering complex genetic libraries to specific tissues in vivo. To overcome these challenges, we describe a simple and versatile intraductal injection strategy that enables efficient and rapid functional genomic screening in the mouse mammary gland, by generating tens of thousands of discrete epithelial clones. Furthermore, we provide all the details necessary for library generation, intraductal injection, screen deconvolution, and analysis of CRISPR-Knockout and Activation libraries for comprehensive in vivo screens. Using these tools, which we termed CRISPR-KOALA (Knockout and Activation Linked Assay), we have identified new tumor suppressors and oncogenes within the coding and non-coding genome in pooled libraries ranging from 46 loci to one-fifth of the genome. Importantly, this approach and analysis can be applied to other organs to study the biological function of any gene during homeostasis or disease.

KRAS G12C has emerged as a clinically important therapeutic target in non-small cell lung cancer (NSCLC), representing a major advance in the treatment of KRAS-driven malignancies. The development of covalent inhibitors targeting the switch-Ⅱ pocket of inactive, GDP-bound KRAS has transformed a previously undruggable oncogene into a molecularly actionable target. First-generation KRAS G12C inhibitors, including sotorasib and adagrasib, have demonstrated clinically meaningful activity in previously treated NSCLC; however, their benefit is limited by acquired resistance, which arises through secondary KRAS alterations, bypass pathway activation, and adaptive reactivation of downstream MAPK signaling. In addition, treatment-related hepatotoxicity, particularly in the setting of prior or closely sequenced immune checkpoint inhibitor exposure, has emerged as an important clinical concern. Multiple next-generation KRAS G12C inhibitors, such as divarasib, glecirasib, and olomorasib, are currently under clinical development, with early evidence suggesting improved potency, selectivity, and tolerability. Furthermore, combination strategies incorporating immune checkpoint inhibitors and upstream or downstream pathway-targeted agents, including SHP2, SOS1, and MEK inhibitors, are being actively investigated to enhance the depth and durability of response. More recently, the advent of RAS (ON) inhibitors, exemplified by daraxonrasib (RMC-6236), has introduced a distinct therapeutic paradigm by directly targeting active RAS through a tri-complex mechanism. As the therapeutic landscape continues to evolve, optimal treatment selection will require integrated consideration of molecular heterogeneity, resistance mechanisms, toxicity profiles, and patient-centered shared decision-making.

miRNAs are short RNA transcripts that modulate gene expression after transcription and have emerged as pivotal regulators of cancer biology. A subset, termed oncomiRNAs, functions as oncogenes or tumor suppressors, influencing key cellular events such as cell growth, programmed cell death, neovascularization, tissue invasion, and metastatic spread. Dysregulation of these miRNAs drives tumor initiation and progression, underscoring their role in cancer evolution. Traditionally, studies have relied on bulk tissue analyses, overlooking the profound spatiotemporal heterogeneity of oncomiRNA expression, including variations across tumor regions, metastatic sites, disease stages, and during treatment. Advances in spatial transcriptomics, single-cell profiling, and longitudinal liquid biopsy technologies have provided new insights into the dynamic regulation of oncomiRNAs. These approaches reveal significant spatiotemporal variability in miRNA expression and are increasingly implicated in shaping tumor heterogeneity, therapeutic resistance, immune evasion, and divergent clinical outcomes. Emerging evidence underscores the importance of integrating these dynamic molecular patterns into biomarker discovery frameworks and precision oncology strategies. Furthermore, the incorporation of artificial intelligence and multi-omics data integration is enhancing patient stratification and predictive modeling. A comprehensive understanding of the spatiotemporal regulation of oncomiRNAs is essential for advancing next-generation cancer diagnostics and therapeutics. Future efforts should focus on systematic multi-region and longitudinal study designs, as well as their integration into adaptive clinical trials. Leveraging these insights may enable miRNA-guided, stage-adapted precision cancer theranostics in heterogeneous malignancies.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy, and its intrinsic variability contributes to aggressive progression, recurrence, and therapeutic resistance. Exosomes are key mediators of intercellular communication among tumor cells with different malignant potentials, while N6-methyladenosine (m6A) modification has emerged as a critical epigenetic regulator of tumorigenesis. However, the mechanisms by which exosome-mediated m6A regulation contributes to HCC progression and heterogeneity remain poorly understood. Exosomal microRNA (miRNA) profiles from HCC cells with distinct malignant phenotypes were analyzed using microarray analysis, and the clinical relevance of miR-769-3p was evaluated in samples of HCC patients. Gain- and loss-of-function assays were performed to assess its effects on HCC proliferation and metastasis both in vitro and in vivo. AlkB homolog 5 (ALKBH5) was identified as a downstream target of miR-769-3p, and its m6A-dependent regulatory mechanism was investigated using methylated RNA immunoprecipitation sequencing and subsequent validation assays. In addition, a liposome-based drug delivery system targeting miR-769-3p was developed and evaluated for therapeutic efficacy. Exosomal miR-769-3p was significantly enriched in highly malignant HCC cells and was associated with poor clinical outcomes. Functional studies demonstrated that exosomal miR-769-3p promoted HCC proliferation and metastasis by suppressing ALKBH5 expression. Mechanistically, ALKBH5 inhibited the expression of the oncogene G protein subunit alpha z (GNAZ) in an m6A-dependent manner, while ALKBH5-mediated destabilization of GNAZ transcripts required the m6A reader insulin-like growth factor 2 mRNA-binding protein 1. Importantly, in vivo experiments revealed that a liposomal delivery system targeting miR-769-3p markedly suppressed HCC tumor growth and metastatic dissemination. Exosomal miR-769-3p mediates malignant intercellular communication between HCC subtypes by regulating the ALKBH5/m6A/GNAZ axis. Targeting miR-769-3p using a liposome-based delivery strategy represents a promising therapeutic approach for HCC. These findings provide novel mechanistic insights into HCC progression and identify a potential therapeutic target for HCC treatment.

Liposomes represent versatile drug delivery shuttles in clinics for cancer therapy. Nevertheless, traditional PEG-modified liposomes encounter difficulties, including (1) poor blood-brain barrier (BBB) transcytosis and tumor targeting without ligand-decoration; (2) accelerated blood clearance (ABC) resulting from anti-PEG antibodies and complement proteins. To overcome these challenges, we employed a ligand-free, BBB-permeable, and glioblastoma (GBM)-targeting zwitterionic polyphosphorylcholine (PMPC)-modified liposomal formulation for siRNA delivery (PMPC-Lipo@siRNA). PMPC-modified formulation leverages interactions with nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) to achieve effective BBB transcytosis and targeted tumor accumulation. Unlike anti-PEG antibodies-induced immunogenicity, PMPC modification successfully circumvents opsonin recognition, which potentially translates into their extended blood circulation and improved therapeutic responses. By targeting the PLK1 oncogene, PMPC-Lipo@siPLK1 effectively induced apoptosis through PLK1 inhibition, significantly extending the median survival of mice in both orthotopic human U87MG and patient-derived CSC2 stem cell xenograft models. Overall, PMPC-modified liposomes provide an effective ligand-free platform for GBM-targeted siRNA delivery by combining prolonged systemic circulation with intrinsic brain-targeting capability, highlighting their potential for RNAi-based therapy against GBM.

Although Poly(A)-binding protein cytoplasmic 1 like (PABPC1L) has been studied in specific cancer types, its broader potential as a prognostic biomarker remains uninvestigated, and the systematic pan-cancer analysis is currently lacking. We performed an integrated pan-cancer analysis of PABPC1L expression and function in 33 human malignant tumors. Associations between PABPC1L expression and tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment composition, drug sensitivity, and response to immune checkpoint blockade (ICB) were also evaluated. A gastric cancer (GC) single-cell RNA sequencing dataset was analyzed to examine the correlation between PABPC1L expression and intercellular communication networks. The relationship between PABPC1L and PD-L1 expression was investigated in human colorectal cancer (CRC) tissue. Functional validation experiments were performed in CRC and GC cell lines. PABPC1L expression was consistently upregulated in multiple cancer types and significantly associated with poor patient prognosis. Notably, PABPC1L was identified as an immunomodulatory factor. It influenced the expression of multiple immune-related genes, regulates immune cell infiltration, and correlates with the outcomes following ICB therapy. Single-cell RNA sequencing analysis of GC further indicated that PABPC1L was involved in intercellular communication networks, including immune cells. In CRC, elevated PABPC1L expression was observed in tumor tissues and positively correlated with PD-L1 levels. Functional experiments confirmed that PABPC1L promoted cell proliferation, regulated cell cycle, and impaired the sensitivity of gastric and colorectal cells to 5-FU. In conclusion, PABPC1L is identified as exhibiting oncogenic properties and is proposed to function as a key regulator of tumorigenesis and immunotherapy resistance.

Regulation of cancer cells by their environment contributes to tumorigenesis and drug response, though the extent to which the oncogenic state can alter a cell's perception of its environment is not clear. EML4-ALK is a receptor tyrosine kinase (RTK) fusion oncoprotein that suppresses transmembrane EGFR signaling in cancer cells. ALK inhibition restores signaling through EGFR, thereby promoting survival and drug tolerance. Here, we tested whether such modulation of EGFR activity was common among other RTK fusions, which collectively are found in ~5% of all cancers. Using live- and fixed-cell microscopy in isogenic and patient-derived cell lines, we found that a wide variety of RTK fusions suppress transmembrane EGFR, through mechanisms that include the sequestration of the adaptor protein Grb2. Targeted therapies rapidly released Grb2 from sequestration and potentiated EGFR. Synthetic optogenetic analogs of RTK fusions confirmed that cytoplasmic sequestration of Grb2 was sufficient to suppress perception of extracellular EGF and could do so without driving signaling from the synthetic fusion itself, demonstrating that fusion signaling and suppression of EGFR signaling could be functionally decoupled. Our study uncovers that a large number of RTK fusions simultaneously act as both activators and suppressors of signaling, the mechanisms of which could be exploited for biomimetic therapies that enhance cell killing and suppress drug tolerance.

An increasing number of octogenarian patients are being diagnosed with lung cancer, but they are less likely to receive surgery because of fragility. As a result, the optimal management of lung cancer in octogenarians remains unclear. Here we report a case of an octogenarian patient with locally advanced non-small-cell lung cancer (NSCLC) who achieved long-term survival via surgery followed by adjuvant targeted therapy. An 82-year-old male patient was admitted to our center for lung cancer surgery in April 2020 at West China Hospital, Sichuan University. He was clinically diagnosed with cT2N1M0(cIIB, AJCC 8th edition) lung cancer in the right lower lobe. Because of his good cardiopulmonary function without comorbidities, the patient was scheduled for thoracoscopic surgery. However, due to tumor invasion into the middle lobe and dense adhesions to the bronchus and vessels, the patient underwent conversion to open thoracotomy and finally received bilobectomy with systematic lymph node dissection. The patient recovered uneventfully and was discharged on postoperative day 5. After surgery, the patient was pathologically diagnosed with pT3N2M0(pIIIB) lung adenocarcinoma harboring an EGFR L858R gene mutation and began adjuvant icotinib. The patient progressed with multiple pulmonary metastasis at 13 months after starting icotinib and his liquid biopsy revealed a T790M mutation; he began treatment with the third-generation EGFR-TKI aumolertinib. In the last follow-up in December 2025, the patient remained on aumolertinib therapy and remained alive without progression. Age alone is not a contraindication for lung cancer surgery and octogenarian patients may tolerate surgical resection following careful preoperative evaluation. Adjuvant targeted therapy may prolong survival in octogenarian lung cancer patients harboring oncogenic driving gene mutation after surgery.

Adult diffuse gliomas remain challenging to treat because of their infiltrative growth and resistance to multimodal therapy. Although GLIPR2 has been implicated in autophagy regulation and tumor-related processes, its role in glioma remains unclear. In this study, transcriptomic and clinical data from TCGA, CGGA, and GTEx were integrated with western blotting and immunohistochemical validation in human glioma specimens. Prognostic significance was evaluated using Kaplan-Meier and ROC analyses. Functional effects of GLIPR2 knockdown were examined in U138 and U251 glioma cells through assays of proliferation, migration, invasion, apoptosis, DNA damage, and clonogenic survival. KEGG enrichment analysis and western blotting were used to investigate associated signaling pathways. GLIPR2 expression was significantly elevated in gliomas, predominantly localized in the cytoplasm, and positively correlated with tumor grade. High GLIPR2 expression was associated with unfavorable overall survival and demonstrated predictive value for 1-, 3-, and 5-year survival. Silencing GLIPR2 inhibited glioma cell proliferation, migration, and invasion while promoting apoptosis. Moreover, GLIPR2 knockdown enhanced irradiation-induced γ-H2AX accumulation and reduced post-irradiation clonogenic survival, indicating impaired resolution of radiation-induced DNA damage and increased radiosensitivity. Mechanistically, GLIPR2 depletion was accompanied by reduced PI3K/AKT pathway activity and lower p-GSK-3β and MMP9 expression, without altering total GSK-3β levels. These findings identify GLIPR2 as a glioma-associated biomarker linked to malignant progression, unfavorable prognosis, and radioresistance and nominate it as an investigational molecular vulnerability for further validation.

Oncogenic mutations of the PIK3CA gene, which encodes the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) enhance cell migration via ERK (ERK1 and ERK2, also known as MAPK3 and MAPK1, respectively) activation. We analyzed the factors regulating collective cell migration (CCM) of genome-edited MCF10A cell lines carrying hotspot PIK3CA mutations E545K or H1047R. H1047R enhanced CCM and promoted the propagation of waves of ERK activity backwards from the wound edge, whereas E545K impaired both coordinated CCM and ERK activity wave formation. The distance traveled by ERK activity waves correlated with directional persistence of migrating cells. Inhibition of cell contractility stimulated ERK wave propagation and efficient CCM of E545K cells but impaired ERK waves and CCM in control cells. Impaired ERK wave propagation was consistently associated with non-linear cell-cell junctions and the loss of polarized distribution of actomyosin. Taken together, these analyses suggest that polarized actomyosin contractility and pulsatile ERK activation must be constrained in the territory of a phase diagram compatible with mechanotransduction of ERK waves across cell-cell junctions to achieve highly coordinated and efficient collective migration.

Despite therapeutic advances in the early-stage triple negative breast cancer (TNBC) setting, residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and is a major obstacle to improving patient outcomes. To better characterize RD and identify survival associated features, we performed comprehensive transcriptomic profiling of 340 pre-treatment stage II/III TNBCs and 70 matched post-treatment RD samples from the randomized CALGB 40603 (Alliance) Phase 2 clinical trial. Preclinical treatment strategies mimicking RD patients were explored using Antibody Drug Conjugate (ADC) treatment in patient derived xenograft (PDX) mouse models. Our study shows that prognostic genomic features measured prior to treatment may differ from prognostic features measured after treatment from RD specimens. Specifically, we identified that patients with a genomic PAM50 subtype of Basal-like in RD specimens have a poor survival outcome and their matching pre-treatment tumors are characterized by elevated chromosomal amplifications of oncogenic drivers (i.e., MYC, CDK6, and CCND1) as well as significantly reduced B- and T-cell expression features. Paired analyses of Basal-like RD and matched pre-treatment tumors reveal further lymphocyte depletion in the RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a Basal-like and conventional chemotherapy-resistant PDX model, resembling Basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response. RD biology differs from pre-treatment tumors, with Basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Pre-clinical modeling suggests that this high-risk group may benefit from adjuvant ADC therapy. ClinicalTrials.gov NCT00861705 Funding: National Cancer Institute (NCI) U10CA180821 (Alliance for Clinical Trials in Oncology) NCI U24CA176171 (Alliance for Clinical Trials in Oncology) NCI UG1CA233373 (Alliance for Clinical Trials in Oncology) NCI Breast SPORE program P50-CA058223 (CMP) Susan G. Komen SAC-160074 (CMP, PDR) Breast Cancer Research Foundation BCRF-23-127 (CMP) NCI R01-CA229409 (CMP) UNC LCCC Triple Negative Breast Cancer Center (CMP).

First identified as a specific modification in 2019, lysine lactylation has gained prominence as a major focus in oncology and epigenetics, building upon more than a century of foundational research on lactate. This Review systematically summarizes recent advances in lysine lactylation research, examining its role in tumor development and its clinical implications. This review integrates and synthesizes the literature from 2019 to 2026, focusing on the roles of lysine lactylation in tumor metabolism, immunological escape and chemoresistance. Once considered a metabolic waste in the tumor microenvironment (TME), lactate now acts as an epigenetic driver by promoting histone lactylation to fuel tumor progression. Research shows that elevated lysine lactylation drives tumor progression, metastasis, immunosuppression, and chemoresistance in multiple cancers. Furthermore, methodological advances, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) and specific antibody-based detection, have propelled the in-depth study of lactylation. As a key oncogenic modulator, lysine lactylation represents an emerging target for precision cancer therapy. Advances in detection and mechanistic insight make lactylation a promising target for precision cancer diagnosis and therapy.