Epidemiological data show that approximately 80% of cancer patients experience pain of varying degrees throughout the course of their disease, with nearly one-third experiencing severe pain, significantly impacting their quality of life and the effectiveness of antitumor treatment. Triple-negative (TN) breast cancer tissues typically exhibit increased stromal stiffness and abnormally elevated mechanical stress; these biomechanical alterations may amplify pain signals by activating mechanosensitive channels. Utilizing single-cell RNA sequencing analysis, this study aims to elucidate the potential biological links between fibroblast mechanotransduction and cancer-associated pain, thereby providing a theoretical basis for clinical diagnosis and treatment.

We reported LINGO1 as a potential marker on Ewing sarcoma cells that could enable targeted drug delivery, improving treatment effectiveness while reducing side effects.

The cGAS/STING pathway is a central innate immune DNA-sensing system that links aberrant DNA species to innate immune and stress-response transcriptional programs and has emerged as a key regulator of tumor-immune interactions. In cancer, pathway outputs are shaped by interconnected downstream signaling modules, including type I IFN, NF-κB, autophagy, and stress-metabolic checkpoints, as well as by stringent spatial and biochemical regulation of both cGAS and STING. When activation is acute and appropriately compartmentalized, cGAS/STING signaling promotes antitumor immunity across multiple cellular compartments in the tumor microenvironment, supporting DC cross-priming and cytotoxic lymphocyte responses. In contrast, chronic or dysregulated activation rewires downstream signaling toward stress-adaptive and inflammatory programs that promote tumor progression, metastasis, and immune dysfunction, including deleterious effects in lymphocytes and the induction of suppressive myeloid and B cell populations. Here, we examine how context determines the consequences of cGAS/STING activation in cancer, review emerging therapeutic strategies that modulate this pathway, and discuss how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation.

Fibroblast growth factor receptor 3 (FGFR3) is one of the most frequently altered genes in bladder cancer, primarily through activating mutations that drive oncogenesis and are enriched in luminal tumors. However, the underlying gene regulatory network (GRN) remains poorly characterized. Here, we constructed an FGFR3-mutated GRN using a bottom-up bioinformatics approach, integrating transcriptomic data from bladder cancer cell lines, FGFR3-mutated tumors, and FGFR3 perturbation experiments in human and mouse models. Using publicly available CRISPR/Cas9 screening data, we identified transcription factors from this GRN that regulate the viability of FGFR3-mutated cells, with a focus on p63 (TP63). We showed that FGFR3 activation upregulates p63 in patient-derived xenografts and cell lines, while single-cell RNA sequencing revealed heterogeneous p63 activation associated with basal differentiation. Functional studies, including TP63 knockdown in FGFR3-dependent in vitro and in vivo models and RNA-seq along with p63 ChIP-seq, demonstrated that p63 directly promotes cell proliferation and migration and uncovered a positive feedback loop between FGFR3 and p63. Together, these findings support p63 as a protumorigenic regulator in FGFR3-mutated tumors despite their luminal differentiation and provide a detailed FGFR3-driven GRN, offering insights into FGFR3-induced oncogenic dependency and potential strategies to circumvent resistance to FGFR inhibitors.

BRAF inhibitors have advanced treatment for patients with BRAF-altered high and low-grade glioma (HGG and LGG, respectively). Clinically-available therapies are effective but require selection by mutation type and careful, proactive toxicity management to maximize patient quality of life and treatment duration. While pediatric LGG patients often experience durable responses, adults with LGG and patients with HGG frequently develop treatment resistance and disease progression while on treatment. Strategies to prevent or overcome resistant disease are under active preclinical and clinical investigation. This review serves as a primer to BRAF-altered therapy in glioma, outlines best practices for using available BRAF inhibitors, and highlights emerging therapeutic approaches aimed at improving outcomes in resistant disease. It serves as a forward-looking, practical guide for clinicians treating patients with BRAF-altered glioma.Article highlightsBRAF inhibitors are effective in both pediatric and adult low- and high-grade gliomas (LGG and HGG), but treatment should be tailored to the specific BRAF alteration (Table 1).Dabrafenib combined with trametinib is FDA-approved for BRAF V600E-mutant gliomas, while tovorafenib is approved for pediatric LGGs harboring BRAF V600 mutations or BRAF fusions.Proactive management, including anticipatory guidance and dose reduction for some patients, is essential to mitigate toxicity and avoid treatment interruptions.Tumor progression can occur during treatment interruptions or drug cessation; however, some patients may respond to BRAF inhibitor rechallenge.Emerging strategies focus on combination with other therapies including radiation, autophagy inhibitors, additional targeted agents, and others to overcome acquired resistance.Next-generation BRAF inhibitors-including paradox breakers, dimer disruptors, and protein degraders-are under clinical investigation (Table 2).

Brady and colleagues investigated the mutational consequences of cancer treatment on the genomes of 160 childhood cancer survivors who developed a subsequent neoplasm (SN). Their research aids in directing the next steps toward the prevention of SNs. See related article by Brady et al., p. 1590.

Beyond established rare fusions, such as ALK and ROS1, emerging ultrarare fusions involving receptor tyrosine kinases or their ligands, including EGFR-SHC1, further guide us to uncover novel mechanisms of oncogenic activation and corresponding treatment strategies. Collectively, rare and ultrarare genomic events are driving precision oncology toward an increasingly individualized era of "ultraprecision" cancer therapy. See related article by Zheng et al., p. 1573.

Metastatic colorectal cancer (mCRC) remains a major contributor to cancer-related mortality worldwide. Real-world data from low- and middle-income countries remain limited.

Thrombotic events are a major morbidity among Philadelphia chromosome-negative myeloproliferative neoplasm (Ph-MPN) patients. There is a lack of data from Kerala regarding the profile of Ph-MPN and the prevalence of thrombosis among these patients.

NTRK fusions drive the pathogenesis of a distinctive group of mesenchymal neoplasms with significant impact on classification and targeted therapy. However, unexpected NTRK fusions have been reported in other sarcoma entities, raising uncertainty over their specificity and clinical management. Herein, we investigate the incidence and structural variants of NTRK fusions among a large clinicopathologic and molecular sarcoma cohort. The goal was to distinguish primary driver NTRK fusions from potential passenger events and correlate with sarcoma histotypes. NTRK1-3 fusions were queried across a large spectrum of sarcomas, profiled by targeted DNA and/or RNAseq. Fusions were classified as oncogenic when NTRK was the 3' partner, in-frame, retained kinase domain (KD), and/or RNAseq confirmation; fusions of uncertain significance (FUS) when out-of-frame, lacking full KD, and/or RNAseq negative. We identified 48 cases with NTRK fusions, detected either by pathologist-initiated RNAseq for diagnosis (n = 27) or by clinician-initiated DNAseq for therapeutic target discovery (n = 21). For the latter subset, reflex RNAseq was activated for confirmation. Integrated review confirmed 33 (69%) oncogenic fusions. Remaining were FUS, apart from one indeterminate. In all except three cases, oncogenic fusions occurred in canonical NTRK-driven histotypes. In contrast, NTRK FUS were detected in various pathologic entities, including well-differentiated/dedifferentiated liposarcoma (n = 9, 60%), two osteosarcoma, and single cases of other subtypes. NTRK1 fusions were the most common in both oncogenic and FUS groups (61%, 67%). CDKN2A/B deletions were observed mostly in oncogenic NTRK1 fusions (71%), while MDM2/CDK4 amplifications in the NTRK1 FUS. The FUS group demonstrated lower NTRK mRNA expression, with a mean of -4.60, p < 0.001. Pan-TRK immunohistochemistry was positive in cases with oncogenic NTRK fusions, and negative in FUS cases. Only two-thirds of NTRK fusions detected were functional drivers, mostly from pathologist-driven testing of suggestive histotypes. In contrast, genomic profiling in complex sarcomas often yields passenger FUS, lacking functional impact.

There is morphological overlap between nodular necrotizing fibroblastic sarcoma (NNFS) and myxoinflammatory fibroblastic sarcoma (MIFS). Whether they represent neoplasms within the same tumor spectrum remains unclear. We performed a comparative clinicopathological, molecular, and epigenetic study of these two tumors.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS), occurring in isolation or as part of Carney complex (CNC); its phenotypic and molecular spectra remain incompletely defined.

TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare, aggressive subtype that predominantly affects adolescents and young adults. Its marked morphologic heterogeneity can delay recognition and downstream confirmatory testing.

Despite remarkable advances in cancer drug treatment, including chemotherapy, targeted therapy, and immunotherapy, therapeutic resistance remains a formidable clinical barrier, limiting durable responses and long-term survival. Drug resistance can be broadly categorized as intrinsic, where tumors fail to respond to initial treatment, or acquired, which emerges during or after therapy due to adaptive or evolutionary processes. A comprehensive understanding of the multifactorial and dynamic nature of resistance is essential for improving treatment efficacy. In this review, we systematically examine the molecular and cellular determinants of drug response and resistance across 22 cancer types, highlighting key resistance mechanisms such as compensatory pathway activation, phenotypic plasticity, immune evasion, enhanced DNA damage repair, and the survival of drug-tolerant persister cells. These mechanisms are further contextualized across major therapeutic modalities, supported by clinical trials. We also present emerging strategies to overcome resistance, including rational drug combinations, novel agents, microbiome modulation, adaptive and intermittent therapies and advanced drug delivery systems, each illustrated with representative clinical studies. Moreover, we discuss cutting-edge tools that are revolutionizing resistance research, including single-cell and spatial multiomic profiling, patient-derived tumor organoid and xenograft (PDO/PDX) models, and artificial intelligence (AI)-powered predictive analytics. By integrating insights across molecular, cellular, and clinical dimensions, this review offers a strategic framework for understanding and tackling cancer drug resistance, with important translational implications for the future of precision oncology.

Despite the widespread adoption of 5-fluorouracil (5-FU)-based regimens as first-line therapy for gastric cancer, a substantial number of patients develop innate or acquired resistance, highlighting the critical need to identify its underlying molecular drivers. RPRD1B (CREPT), a gene frequently overexpressed in GC, has been clinically associated with advanced tumor stage and poor prognosis. Functionally, RPRD1B promotes aggressive tumorigenic phenotypes by accelerating cell-cycle progression, potentiating proliferative signaling, and enhancing the migratory and invasive capacities of cancer cells. However, its functional role in mediating chemotherapy resistance has not been elucidated.

Tumour necrosis factor (TNF) is a pleiotropic cytokine originally identified for its ability to kill cancer cells. However, a paradoxical tumour-promoting role for TNF emerged when early attempts to exploit its anti-tumour activity in cancer therapy produced conflicting outcomes, raising the question of whether TNF should be viewed as a therapeutic agent or a treatment target in cancer. Here, we demonstrate that expression of cFLIP, a catalytically inactive paralogue of caspase-8 (CASP8), determines the susceptibility of melanoma cells to TNF and thereby controls melanoma growth in a syngeneic, immune-competent mouse model of B16F10 cutaneous melanoma. B16F10 melanoma cells lacking cFLIP (cFlipKO/KO cells) failed to grow in wild-type mice, whereas in TNF-deficient mice, cFlipKO/KO melanoma cells formed palpable tumours and exhibited robust subcutaneous growth. These findings indicate that TNF alone is sufficient to control melanoma growth in the absence of cFLIP. Importantly, the anti-tumour activity of TNF has predominantly been investigated through targeting cellular inhibitors of apoptosis proteins (cIAPs), which promotes RIPK1 activation and TNF-induced cytotoxicity. We show that genomic ablation of cIAPs or RIPK1, in contrast to cFLIP, neither triggered TNF-induced toxicity nor affected melanoma growth in vivo. Collectively, our data underscore the central role of cFLIP in regulating melanoma responses to TNF and suggest that endogenous immune surveillance as well as immunotherapies involving TNF could strongly benefit from cFLIP targeting strategies.

Glioblastoma is the most aggressive primary brain tumor in adults. Resistance of glioblastoma to the standard chemotherapy agent temozolomide (TMZ) correlates with the expression of the DNA repair enzyme O6-Methylguanine-DNA methyltransferase (MGMT). Additionally, tumor initiation and recurrence are associated with a subpopulation of glioblastoma stem cells (GSCs) which exhibit self-renewal properties, multipotency, and resistance to both chemotherapy and radiotherapy. To identify novel molecular biomarkers and therapeutic targets, we investigated the possible role of the oncoprotein Golgi phosphoprotein 3 (GOLPH3) in glioblastoma. GOLPH3 is overexpressed in many solid tumors and confers resistance to DNA-damaging chemotherapeutic agents. Its overexpression is also associated with poor prognosis in a variety of cancers, including glioblastoma. Here, we show that GOLPH3 knockdown in U87MG glioblastoma cells inhibits cell proliferation, promotes senescence and induces striking cellular and molecular changes toward a neuron-like phenotype. We analyzed the constitutive expression of GOLPH3, MGMT and mechanistic target of rapamycin (mTOR) signaling proteins in U87MG cells and in three GSCs representative of the three glioblastoma molecular subtypes. Our results suggest that these glioblastoma cell models may exhibit distinct responses to mTOR inhibition and TMZ. Finally, we show that GOLPH3 depletion reduces the activity of both mTOR complex 1 and 2 leading to decreased phosphorylation of their respective downstream targets S6K and Akt in both U87MG cells and the BT379 GSCs subtype. Our findings identify a potential therapeutic vulnerability that can be exploited to develop patient-tailored treatments in glioblastoma.

Simultaneous imaging of multiple intracellular RNA biomarkers is essential for precise molecular subtyping of cancers, but achieving orthogonal signal amplification with a low background remains a challenge. Herein, we design an entropy-driven palindromic DNA nanostructure by integrating four orthogonal catalytic circuits into a single nanostructure for accurate discrimination of different breast cancer cell subtypes based on multiplexed imaging of miRNA-21, miRNA-373, miRNA-155, and MnSOD mRNA. This system is constructed from two cruciform modules. Cruciform module 1 is formed by four substrate complexes with each consisting of a quencher-labeled template, a fluorophore-labeled reporter (Alexa Fluor 405, 488, 568, and 647) and an assistant strand carrying a palindromic arm for co-localizing the fluorophores and quenchers to suppress fluorescence. Cruciform module 2 is assembled from four fuel strands sharing the same palindromic sequence. Hybridization of two modules via their complementary palindromic arms generates self-assembled palindromic DNA nanostructure (SAPDN). Upon cellular internalization of SAPDN, each target RNA binds a specific toehold on its corresponding substrate complex to trigger an entropy-driven strand-displacement cascade, releasing a target-probe intermediate. Subsequent invasion by the fuel strand results in the liberation of intact target, the displacement of reporter strand, and the separation of fluorophore from the quencher to restore fluorescence. The liberated RNA targets can activate new substrate complexes to achieve catalytic signal amplification. By mapping the four fluorescence signatures inside living cells, the SAPDN platform can effectively differentiate different breast cancer subtypes, holding great promise in advanced molecular diagnostics.

Lipid metabolic reprogramming is a hallmark of cancer, in which fatty acid synthesis is crucial for the rapid proliferation and metastasis of cancer cells. The p53-R280K mutation drives aggressive cancer, yet its role in fatty acid synthesis remains unclear.

Acute lymphoblastic leukemia is the most common pediatric hematological disease representing less than 1% of hematological diseases in adults. The prognosis of ALL improved significantly in the last decades. Almost all patients require a therapy at the time of diagnosis. Rare cases of spontaneous remission of ALL have been described. We report a case of B-ALL that underwent spontaneous remission after an episode of infection and describe the cytogenetic changes associated with this uncommon clinical presentation of B-ALL.