Lingzhi Wang

Purpose: MAPK pathway activation suppresses iodine-handling genes, including sodium-iodide symporter (NIS), contributing to loss of iodine avidity in radioiodine-refractory thyroid cancer. Prior BRAF/ MEK inhibitor re-differentiation trials improved iodine uptake but used empiric 4–6 week treatment. The timing of maximal NIS re-expression remains undefined. We evaluated whether short course dabrafenib plus trametinib restores iodine uptake and provides clinical benefit. Patients and Methods: In this multicentre phase II trial, patients with progressive metastatic radioiodine-refractory thyroid carcinoma harbouring BRAFV600E or RAS mutations received dabrafenib and trametinib. I-124 PET/CT dosimetry was performed at baseline and after 2 weeks, with repeat imaging at week 4 post therapy if dosimetry criteria was not met. Radioiodine was administered once criteria was met. The primary endpoint was attainment of predicted lesional absorbed dose ≥20 Gy with I-131 activity ≤300 mCi. Secondary endpoints included RECIST response, progression-free survival (PFS), thyroglobulin response, and safety. Results: Nine of 14 patients (64%) met the dosimetry criteria and received radioiodine; 6 out of 9 (67%) restored iodine uptake within 2 weeks. Among radioiodine-treated patients, best objective response rate within 6 months was 75% by RECIST. Median PFS was 10.8 months. RAS-mutant tumours demonstrated greater lesion regression than BRAFV600E-mutant tumours. Early reduction in stimulated thyroglobulin and preserved FOXE1 nuclear localisation, and higher tumour-to-normal GLIS3 nuclear expression were associated with re-differentiation response. Conclusions: Short-course dabrafenib/ trametinib can induce rapid re-differentiation within 2 weeks in a subset of patients with MAPK-driven radioiodine-refractory thyroid cancer, supporting individualized BRAF/MEK inhibition duration rather than empiric prolonged treatment.

Lutetium-177 ( ¹⁷⁷ Lu)–based Radioligand Therapy (RLT) has emerged as an important modality in precision oncology, with demonstrated clinical benefit in selected malignancies. Its clinical relevance is underscored by regulatory approvals of Lutathera® for neuroendocrine tumours and Pluvicto® for metastatic castration-resistant prostate cancer. However, despite these advances, the field faces significant challenges that limit broader clinical translation and optimisation. In this review, we provide a critical and balanced evaluation of the current ¹⁷⁷ Lu RLT landscape, integrating evidence from clinical trials, emerging targets, and translational studies. We highlight that much of the existing evidence is derived from small, non-randomised studies with inherent risk of bias, limiting the strength of clinical conclusions. Key challenges include the lack of standardised and clinically actionable dosimetry, insufficient predictive biomarkers beyond target expression, vulnerability of isotope supply chains, and the development of drug-evasive traits in malignant cells. In addition, heterogeneity in trial design and limited long-term safety data further constrain clinical implementation. We propose a strategic roadmap to advance ¹⁷⁷ Lu RLT toward a more rigorous, reproducible, and equitable precision oncology framework, emphasising the transition from empiric application to evidence-based personalisation.

Regulatory T cells (Tregs) are central mediators of immune tolerance and key drivers of tumor immune evasion in non-small cell lung cancer (NSCLC). Within the tumor microenvironment (TME), Tregs accumulate and suppress antitumor responses, thereby limiting the durability of immune checkpoint inhibitor (ICI) responses. Emerging evidence indicates that Treg influence on immunotherapy outcomes extends beyond numerical abundance to involve a dynamic Treg-cell death axis, in which enhanced Treg survival and resistance to regulated cell death are coupled with dysfunction, exhaustion, or attrition of effector T cells. Tumor-derived chemokines, cytokines, and metabolic cues promote recruitment, stabilization, and metabolic fitness of Tregs, enabling their persistence within hypoxic and nutrient-deprived niches. Concurrently, Tregs suppress antigen-presenting cell activation, amplify checkpoint signaling, and exploit metabolic and redox adaptations including ferroptosis resistance to maintain immunosuppressive dominance under therapeutic pressure. Together, these mechanisms establish a survival-advantaged regulatory compartment that drives immune cell-fate asymmetry within the TME and limits the durability of immune checkpoint blockade. We propose the Treg-cell death axis as a unifying framework linking immune tolerance, regulated cell death, and immunotherapy resistance in lung cancer. Targeting this axis through mechanism-matched strategies that destabilize tumor-resident Tregs while preserving systemic immune homeostasis may provide new opportunities to overcome therapeutic resistance and improve clinical outcomes.

This file contains supplementary methods, Figs. S1 to S6 and Tables S1 to S5.

Digestive system cancers—including gastric, liver, colorectal, esophageal, and pancreatic malignancies—remain leading causes of cancer death, with treatment resistance posing major challenges in advanced disease. Patient-derived cancer organoids (PDCOs), 3D mini-tumors grown from patient biopsies, have revolutionized personalized oncology by faithfully replicating tumor biology and enabling predictive drug testing for chemotherapy, radiotherapy, targeted therapy, and immunotherapy. While demonstrating good predictive accuracy, current limitations include incomplete tumor microenvironments, variable establishment rates, and lengthy processing times. Emerging technologies like AI, organ-on-chip systems, and 3D bioprinting are addressing these challenges, while clinical trials explore applications in neoadjuvant therapy and real-time treatment guidance. This Review highlights key advances in PDCO technology and its transformative potential for treatment decision-making in digestive system cancers, bridging laboratory research with clinical care to enable truly personalized therapeutic strategies tailored to individual tumor biology.

Glioblastoma (GBM) is a prevalent type of malignancy within the central nervous system (CNS) that is associated with a poor prognosis. The standard treatment for GBM includes the surgical resection of the tumor, followed by radiotherapy and chemotherapy; yet, despite these interventions, overall treatment outcomes remain suboptimal. The blood–brain barrier (BBB), which plays a crucial role in maintaining the stability of brain tissue under normal physiological conditions of the CNS, also poses a significant obstacle to the effective delivery of therapeutic agents to GBMs. Recent preclinical studies have demonstrated that nanomedicine delivery systems (NDDSs) offer promising results, demonstrating both effective GBM targeting and safety, thereby presenting a potential solution for targeted drug delivery. In this review, we first explore the various strategies employed in preclinical studies to overcome the BBB for drug delivery. Subsequently, the results of the clinical translation of NDDSs are summarized, highlighting the progress made. Finally, we discuss potential strategies for advancing the development of NDDSs and accelerating their translational research through well-designed clinical trials in GBM therapy.