Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major challenge in the treatment of lung cancer. Cancer associated fibroblasts (CAFs) play a key role in promoting resistance to anti-cancer therapies. This study identified a subpopulation of CAFs characterized by the overexpression of collagen triple helix repeat-containing 1 (CTHRC1) through single-cell RNA sequencing of lung cancer patients undergoing EGFR-TKI treatment. These CTHRC1+ CAFs were enriched in drug-resistant tumors. Mechanistically, CTHRC1+ CAFs enhance the glycolytic activity of cancer cells by activating the TGF-β/Smad3 signaling pathway. Excess lactate produced in the process of glycolysis further upregulates CTHRC1 expression in CAFs through histone lactylation, creating a positive feedback loop that sustains EGFR-TKI resistance. The study also demonstrated that Gambogenic Acid, a natural compound, can disrupt this feedback loop, thereby improving the efficacy of EGFR-TKI therapy. Additionally, the presence of CTHRC1+ CAFs in tumor tissues could serve as a biomarker for predicting the response to EGFR-TKI therapy and patient prognosis. Overall, this study highlights the significant role of CAFs in EGFR-TKI resistance and suggests that targeting CTHRC1+ CAFs could be a promising strategy to overcome drug resistance in lung cancer.
© 2025. The Author(s).

Arteriovenous malformations (AVMs) are characteristic of hereditary hemorrhagic telangiectasia. Loss-of-function mutations in the activin receptor-like kinase 1 (Alk1) are linked to hemorrhagic telangiectasia type 2.
Endothelial-specific deletion of Alk1, endothelial lineage tracing, transcriptomics of single-cell analysis, and electron microscopy were performed to examine the vascular phenotype and characteristics of ALK1-deficient endothelial cells (ECs) after EC-specific Alk1 deletion. Ischemia assays were used to examine the cell capacity for vascular malformation. Connectivity Map with transcriptomic analysis was applied to identify chemical compounds. Specific methods for arteriovenous malformations, such as micro-computed tomography, with other molecular and cell biological tools were also performed.
We performed endothelial-specific deletion of Alk1 in mice and found severe arteriovenous malformations and vascular leakage. The transcriptomics of single-cell analysis revealed a new distinctive cell cluster formed after Alk1 deletion where the cells coexpressed arterial and lymphatic endothelial markers. The analysis projected that these cells potentially originated from arterial ECs after Alk1 deletion. This new population was referred to as arterial-lymphatic-like ECs according to its cellular markers, and its appearance was validated in the pulmonary small arteries after Alk1 deletion. Transplantation of these cells caused vascular malformations. Endothelial lineage tracing confirmed that these new arterial-lymphatic-like ECs were derived from ALK1 depleted ECs, potentially arterial ECs. We discovered that SOX17 (SRY-box transcription factor 17) induction was responsible for the derivation of these arterial-lymphatic-like ECs. We showed that direct binding of MDM2 (mouse double minute 2) was required for Sox17 to execute this activity. Inhibition of MDM2 reduced the arteriovenous malformations in the mouse model.
Together, our studies revealed the mechanistic underpinnings of ALK1 signaling in regulating the endothelial phenotype and provided possibilities for new therapeutic strategies in hemorrhagic telangiectasia type 2.

Multiple genetic associations suggest a causative relationship between Th17-related genes coding for proteins, such as IL-17A, IL-23 and STAT3, and psoriasis. Further support for this link comes from the findings that neutralizing antibodies directed against IL-17A, IL-17RA and IL-23 are efficacious in diseases like psoriasis, psoriatic arthritis and ankylosing spondylitis. RORγt is a centrally positioned transcription factor driving Th17 polarization and cytokine secretion and modulation of RORγt may thus provide additional benefit to patients. However, RORγt also plays a role in the normal development of T cells in the thymus and genetic disruption of RORγt in the mouse leads to the development of lymphoma originating in the thymus. Whilst it is not established that down-regulation of RORγt activity would lead to the same consequence in humans, further understanding of the thymus effects is desirable to support progress of this target as a potential treatment of Th17-driven disease. Herein we present the characterisation of recently disclosed RORγt inverse agonists demonstrating target engagement and efficacy in vitro and in vivo against Th17 endpoints but requiring higher concentrations in vitro to affect thymocyte apoptosis.
Copyright: © 2025 Collins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The hypoxic and immunosuppressive tumor microenvironment (TME) remains a major obstacle to impede cancer immunotherapy. Here, we found that sononeoperfusion-a new effect of tumor perfusion enhancement induced by low mechanical index ultrasound stimulated microbubble cavitation (USMC)-ameliorated tumor tissue oxygenation and induced tumor vascular normalization (TVN). This TVN might be associated with the down-regulation of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) within tumors. Moreover, the sononeoperfusion effect reduced the accumulation of immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2-like tumor-associated macrophages (M2-TAMs), and decreased the production of immune inhibitory factors like transforming growth factor-β1 (TGF-β1), interleukin 10 (IL-10), chemoattractant chemokines CC-chemokine ligand 22 (CCL22), CCL28, adenosine and lactate within tumors. Notably, flow cytometry analysis revealed that sononeoperfusion not only increased the percentage of tumor infiltrating-CD8+ T cells, but also promoted the generation of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) by these cells. Furthermore, the improved immune TME by sononeoperfusion effect sensitized anti-PD-L1 treatment both in MC38 colon cancer and Lewis lung carcinoma mice, resulting in tumor regression and prolonged survival. Mechanically, the enhanced efficacy of combination therapy was mainly based on promoting the infiltration and function of CD8+ T cells within tumors. Together, sononeoperfusion could ameliorate hypoxia and immunosuppression in the TME, thereby potentiating anti-PD-L1 therapy for solid tumors. This novel method of USMC generating sononeoperfusion effect may provide a new therapeutic modality for facilitating cancer immunotherapy.
Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Limited immune infiltration within the tumor microenvironment (TME) hampers the efficacy of immune checkpoint blockade (ICB) therapy. To enhance immune infiltration, mild photothermal therapy (PTT) is often combined with immunotherapy. However, the impact of mild PTT on the TME remains unclear. The bioinformatics analyses reveal that mild PTT amplifies immune cell infiltration and stimulates T-cell activity. Notably, it accelerates the release of tumor cell-derived exosomes (TEX) and upregulates PD-L1 expression on both tumor cells and TEX. Consequently, it is proposed that locally inhibiting TEX release is crucial for overcoming the adverse effects of mild PTT, thereby enhancing ICB therapy. Thus, a multi-stage drug delivery system is designed that concurrently delivers photosensitizers (reduced graphene oxide nanosheets, NRGO), anti-PD-L1 antibodies, and exosome inhibitors (sulfisoxazole). The system employs a temperature-sensitive lipid gel as the primary carrier, with NRGO serving as a secondary carrier that supports photothermal conversion and incorporation of sulfisoxazole. Importantly, controlled drug release is achieved using near-infrared radiation. The findings indicate that this local combination therapy remodels the immunosuppressive TME through exosome inhibition and enhanced immune cell infiltration, while also boosting T-cell activity to trigger systemic antitumor immunity, showcasing the remarkable efficacy of this combination strategy in eradicating cold tumors.
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.