Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy. Nintedanib, a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors, has yet to be investigated in combination with radiotherapy. This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy.

Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo. Reactive oxygen species (ROS), lipid peroxidation assays, and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death. Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms.

The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo. Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4, the expression of which was elevated in response to radiation as an adaptive mechanism. Consequently, nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells.

These findings support the use of nintedanib in combination with radiotherapy as an effective, low-toxicity treatment strategy, highlighting the antitumor potential of ATF4-targeted agents.

Large-scale CRISPR screens have identified essential genes across cancer cell lines, but links between tumor functional properties and specific dependencies require investigation to reveal the mechanisms underlying dependencies and broaden understanding of targeted therapy.

We selected 47 breast cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) with multi-omics data including gene dependency; somatic mutations; copy number alterations; and transcriptomic, proteomic, metabolomic, and methylation data. We established a dependency marker association (DMA) analytic pipeline by using linear regression modeling to assess associations between 3,874 representative gene dependencies and multi-omics markers. Additionally, we conducted non-negative matrix factorization clustering, to stratify breast cancer cell lines according to gene dependency features, and investigated cluster-specific DMAs.

We interpreted valuable DMAs according to two primary aspects. First, dependencies associated with gain-of-function alterations revealed addiction to lactate transporter SLC16A3, thus suggesting a promising therapeutic target. Second, dependencies associated with loss-of-function alterations included synthetic lethality (SL), collateral SL, and prioritized metabolic SL, encompassing paralog SL (e.g., IMPDH1 and IMPDH2), single pathway SL (e.g., GFPT1 and UAP1), and alternative pathway SL (e.g., GPI and PGD). DMA analysis of the two clusters with divergent dependency signatures demonstrated that cluster1 cell lines exhibited extensive metabolism with mitochondrial protein dependencies, whereas cluster2 displays enhanced cell signaling, and reliance on DNA replication and membrane organelle regulators.

We established a DMA analysis pipeline linking the gene dependencies of breast cancer cell lines to multi-omics characteristics, thus elucidating the underpinnings of tumor dependencies and offering a valuable resource for developing novel precision treatment strategies incorporating relevant markers.

This study aimed at exploring the effects of the epigenetic regulator, chidamide, on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer (SCLC), particularly the roles in macrophage polarization and angiogenesis. The therapeutic efficacy of combining chidamide with the anti-angiogenic agent, anlotinib, for refractory SCLC was also evaluated.

RNA sequencing and functional validation were performed to assess chidamide’s effects on macrophages. Signal transducer and activator of transcription 4 (STAT4)-mediated transcriptional activation of CCL2 was confirmed with ChIP-qPCR. The synergistic efficacy of chidamide in combination with anlotinib was tested in preclinical models.

Chidamide enhanced macrophage infiltration and induced macrophage polarization toward the anti-tumor M1 phenotype. Mechanistically, chidamide upregulated CCL2 via STAT4 transcriptional activation, thereby reshaping the tumor immune microenvironment (TIME). Combining chidamide with anlotinib synergistically suppressed tumor growth and remodeled the immunosuppressive TME in SCLC in vivo.

Chidamide reshaped the SCLC TIME by activating STAT4/CCL2, thus driving M1 macrophage polarization and enhancing anti-tumor immunity. Our findings highlight coordinated TIME-targeted therapy as a translatable strategy to overcome therapeutic resistance in SCLC and provide a rationale for clinical trials examining epigenetic and anti-angiogenic therapeutics combinations.

CLT-003 is a novel phenylphthalimide derivative encapsulated in poly (lactate-glycolic acid) copolymer nanoparticles using nanotechnology techniques. CLT-003 possesses anti-angiogenetic and antitumor activities. Nevertheless, the role and molecular mechanism underlying CLT-003 in pancreatic cancer remain to be elucidated.

Cell proliferation and apoptosis were detected using CCK-8, real-time cell analysis (RTCA), EdU, and flow cytometric assays. Cellular mobility and invasive capacity were detected using wound-healing, Transwell, and cell motility assays. Tumor growth and metastasis were determined using the mouse subcutaneous and pancreatic cancer orthotopic liver metastasis models. The antitumor effects of CLT-003 were evaluated using patient-derived organoid (PDO) and patient-derived xenograft (PDX) models.

CLT-003 significantly inhibited cellular proliferation, enhanced cellular apoptosis, and attenuated cellular invasion and migration of pancreatic cancer cells. Mechanistically, CLT-003 suppressed the translation of HIF-1α by inhibiting the PI3K/AKT/mTOR signaling pathway. In the mouse tumor models, CLT-003 significantly inhibited the growth and metastasis of pancreatic tumors. Moreover, the PDO and PDX models showed increased sensitivity to CLT-003 in pancreatic cancer with high HIF-1α expression compared to pancreatic cancer with low HIF-1α expression.

This study delineated the role and molecular mechanism of CLT-003 action in impeding the progression of pancreatic cancer and indicated its robust potential for the treatment of pancreatic cancer.