Objectives: Chordoma is a rare bone malignancy that affects the spine and skull base. Treatment dilemma leads to a high rate of local relapse and distant metastases. Molecular targeted therapy (MTT) is an option for advanced chordoma, but its therapeutic efficacy and safety have not been investigated systematically. Therefore, a systematic review was conducted on studies reporting MTT regimens for chordoma. Methods: Clinical trials, case series and case reports on chordoma MTT were identified using MEDLINE, Cochrane library and EMBASE, and systematically reviewed. Data on clinical outcomes, such as median overall survival, progression-free survival, response rate and adverse events (AEs) were extracted and analyzed. Results: Thirty-three eligible studies were selected for the systematic review, which indicated that imatinib and erlotinib were the most frequently used molecular targeted inhibitors (MTIs) for chordoma. For PDGFR-positive and/or EGFR-positive chordoma, clinical benefits were achieved with acceptable AEs. Monotherapy is preferred as the first-line of treatment, and combined drug therapy as the second-line treatment. In addition, the brachyury vaccine has shown promising results. Conclusions: The selection of MTIs for patients with advanced or relapsed chordoma should be based on gene mutation screening and immunohistochemistry (IHC). Monotherapy of TKIs is recommended as the first-line management, and combination therapy (two TKIs or TKI plus mTOR inhibitor) may be the choice for drug-resistant chordoma. Brachyury vaccine is a promising therapeutic strategy and requires more clinical trials to evaluate its safety and efficacy.

Background: Kidney renal clear cell carcinoma (KIRC) is the malignancy originated from the renal epithelium, with a high rate of distant metastasis. Aberrant alternative splicing (AS) of pre-mRNA are widely reported to be involved in the tumorigenesis and metastasis of multiple cancers. The aim of this study is to explore the mechanism of alternative splicing events (ASEs) underlying tumorigenesis and metastasis of KIRC. Methods: RNA-seq of 537 KIRC samples downloaded from the TCGA database and ASEs data from the TCGASpliceSeq database were used to identify ASEs in patients with KIRC. The univariate and Lasso regression analysis were used to screen the most significant overall survival-related ASEs (OS-SEs). Based on those, the OS-SEs model was proposed. The interaction network of OS-SEs and splicing factors (SFs) with absolute value of correlation coefficient value >0.750 was constructed by Pearson correlation analysis. The OS-SEs significantly related to distant metastasis and clinical stage were identified by non-parametric test, and those were also integrated into co-expression analysis with prognosis-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways identified by Gene Set Variation Analysis (GSVA). ASEs with significance were selected for multiple online database validation. Results: A total of prognostic 6,081 overall survival-related ASEs (OS-SEs) were identified by univariate Cox regression analysis and a prediction model was constructed based on 5 OS-SEs screened by Lasso regression with the Area Under Curve of 0.788. Its risk score was also illustrated to be an independent predictor, which the good reliability of the model. Among 390 identified candidate SFs, DExD-Box Helicase 39B (DDX39B) was significantly correlated with OS and metastasis. After external database validation, Retained Intron of Ras Homolog Family Member T2 (RHOT2) and T-Cell Immune Regulator 1 (TCIRG1) were identified. In the co-expression analysis, overlapped co-expression signal pathways for RHOT2 and TCIRG1 were sphingolipid metabolism and N-glycan biosynthesis. Conclusions: Based on the results of comprehensive bioinformatic analysis, we proposed that aberrant DDX39B regulated RHOT2-32938-RI and TCIRG1-17288-RI might be associated with the tumorigenesis, metastasis, and poor prognosis of KIRC via sphingolipid metabolism or N-glycan biosynthesis pathway.

Soft tissue sarcoma (STS) is one of the most challenging tumors for medical oncologists, with a high rate of recurrence after initial resection. In this study, a recurrent STS-specific competitive endogenous RNA (ceRNA) network including seven recurrence and overall survival (OS)-associated genes (LPP-AS2, MUC1, GAB2, hsa-let-7i-5p, hsa-let-7f-5p, hsa-miR-101-3p and hsa-miR-1226-3p) was established based on the gene expression profiling of 259 primary sarcomas and 3 local recurrence samples from the TCGA database. The algorithm "cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT)" was applied to estimate the fraction of immune cells in sarcomas. Based on 5 recurrence and OS-associated immune cells (NK cells activated, dendritic cells resting, mast cells resting, mast cells activated and macrophages M1), we constructed a recurrent STS-specific immune cells network. Both nomograms were identified to have good reliabilities (Area Under Curve (AUC) of 5-year survival is 0.724 and 0.773, respectively). Then the co-expression analysis was performed to identify the potential regulation network among recurrent STS-specific immune cells and ceRNAs. Hsa-miR-1226-3p and MUC1 were significantly correlated and dendritic cells resting was related to hsa-miR-1226-3p. Additionally, the expression of MUC1 and dendritic cell marker CD11c were also verified by immunohistochemistry (IHC) assay and multidimensional databases. In conclusion, this study illustrated the potential mechanism of hsa-miR-1226-3p regulating MUC1 and dendritic cells resting might play an important role in STS recurrence. These findings might provide potential prognostic biomarkers and therapeutic targets for recurrent STS.

Background: Chordoma is a rare mesenchymal malignancy, with a high recurrence rate and unclear tumorigenic mechanism. Genetic alterations, epigenetic regulators, and chromatin spatial organization play crucial roles in the initiation and progression of chordoma. In the current study, we aim to uncover the novel therapeutical targets for chordoma via using integrated multi-omics analysis. Methods: The RNA-sequencing (RNA-seq), assay for transposable accessible chromatin by high-throughput sequencing (ATAC-seq), and Hi-C were performed between chordoma and human nucleus pulposus (HNP), along with imageological examination and clinical information. The expressions of identified targets were validated by clinical samples and their functions were further evaluated by cell and animal experiments via gene knockdown and inhibitors. Results: The integrated multi-omics analysis revealed the important roles of bone microenvironment in chordoma tumorigenesis. By comparing the hierarchical structures, CA2 (carbonic anhydrase II) and THNSL2 (threonine synthase-like 2) were identified in the switched compartments, cell-specific boundaries, and loops. Additionally, CA2 was highly expressed in chordoma but barely found in HNP. The cell growth and migration of chordoma cells were dramatically suppressed via inhibition of CA2 either with genetic deletion or pharmaceutical treatment with Dorzolamide HCl. Furthermore, Dorzolamide HCl also regulated the bone microenvironment by blocking the osteoclast differentiation of bone marrow monocytes. Conclusion: This study uncovers the roles of bone microenvironment in the chordoma tumorigenesis and identifies CA2 as a novel therapeutic target for chordoma. Besides, our findings suggest Dorzolamide HCl as a promising therapeutic option for chordoma.

• The bone microenvironment (BME) is a critical driver in bone tumor progression and metastatic spread. • Tumor cells exploit immune, stromal, and metabolic niches to sustain survival and advance progression. • Interactions among senescent osteocytes, bone-resident lymphocytes, and tumor cells shape dormancy and relapse. • Targeting key microenvironmental factors holds promise for improving bone metastasis therapy.

The nervous system is increasingly recognized as a key regulator of the tumor microenvironment, engaging in bidirectional crosstalk with cancer cells through neurotransmitters, neuropeptides, and synaptic-like connections. Autonomic nerves modulate tumor progression: sympathetic signaling promotes growth, metastasis, and immune evasion via β-adrenergic receptor activation, while parasympathetic input exerts dual roles—driving gastric cancer yet protecting against colitis-associated colorectal cancer through the cholinergic anti-inflammatory pathway. Sensory nerves influence pain, angiogenesis, and immunity, with CGRP and substance P differentially regulating anti-tumor responses. Notably, functional neuro-glioma synapses have been identified, where neuronal glutamate release activates AMPA receptors on tumor cells, triggering Ca²⁺ influx and oncogenic signaling—providing a mechanistic basis for repurposing AMPA antagonists like perampanel. Glial cells, including Schwann cells and astrocytes, support perineural invasion, metabolic coupling, and therapy resistance via neurotrophic factor secretion and extracellular matrix remodeling. Tumor-derived signals reciprocally rewire neural circuits, enhancing innervation and neuroplasticity. Central brain regions, such as the paraventricular nucleus, integrate stress inputs to systemically regulate tumor immunity and metabolism through autonomic output. This dynamic interplay positions the nervous system as a master regulator of cancer biology. Targeting neural-tumor interactions—via β-blockers, neuromodulation, or bioelectronic medicine—offers novel therapeutic strategies. Future precision oncology approaches must consider tumor type, stage, and neural context to effectively disrupt this crosstalk and the emerging concept of cancer-induced nerve injury (CINI) as a novel mechanism of immunotherapy resistance.