Yan Yu

PURPOSE: MET amplification accounts for up to 30% of acquired resistance to EGFR-TKI, especially following third-generation EGFR-TKI treatment, yet precision-targeted therapeutic options remain limited. Early-phase studies demonstrated promising antitumor activity with the MET-TKI dalmelitinib combined with the third-generation EGFR-TKI aumolertinib. This phase 3 trial compared dalmelitinib-aumolertinib with platinum-based chemotherapy in EGFR -mutated, MET -amplified advanced NSCLC after EGFR-TKIs progression. PATIENTS AND METHODS: This randomized, open-label, phase 3 trial ( NCT06110663 ) enrolled patients with locally advanced or metastatic EGFR -mutated, MET -amplified NSCLC after EGFR-TKI progression. MET amplification was defined by fluorescence in situ hybridization as a mean MET copy number ≥5 or MET / CEP7 ratio ≥2. Patients were randomly assigned (1:1) to dalmelitinib-aumolertinib or platinum-based chemotherapy groups. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review per RECIST 1.1. Secondary endpoints included overall survival, objective response rate (ORR), duration of response (DoR), and safety. RESULTS: A total of 314 enrolled patients were assigned to dalmelitinib-aumolertinib (n=156) or platinum-based chemotherapy (n=158). Median follow-up was 11.2 months at the data cutoff date (December 10, 2025). Median PFS was 6.2 months with dalmelitinib-aumolertinib and 4.4 months with chemotherapy (HR, 0.60; 95% CI, 0.45 to 0.81; P EGFR -mutated, MET -amplified NSCLC after progression on EGFR-TKI. These findings support dual EGFR/ MET inhibition as a new treatment option in this biomarker selected population.

Although immune checkpoint inhibitors have improved outcomes in lung adenocarcinoma (LUAD), many patients still exhibit inadequate responses. The immunomodulatory functions of RNA‐binding motif (RBM) proteins remain poorly understood. Using in vivo and in vitro models of RBM10 deficiency combined with cytokine arrays, CLIP‐seq, RIP, and proteomics, we found that RBM10 deficiency promotes an immunosuppressive microenvironment, and targeting key chemokines restored anti‐PD‐1 efficacy in RBM10‐deficient LUAD models. RBM10 deficiency enhanced the polarization and recruitment of M2 tumor‐associated macrophages (TAMs), both in vitro and in vivo. Mechanistically, RBM10 loss disrupted STING exon 3 exclusion via alternative splicing and impaired QKI‐mediated stabilization of the STING‐E3(‐) isoform, shifting the splicing balance toward the STING‐E3(+) isoform and promoting CCL7 secretion. CCL7 acted through its receptor CCR2 on macrophages, driving M2 polarization and recruitment. This central pathway was further reinforced by a positive feedback loop wherein M2‐polarized TAMs transferred mitochondria to tumor cells, potentially contributing to mtDNA‐cGAS‐STING signaling and sustained CCL7 production. Therapeutically, CCL7/CCR2 blockade synergized with PD‐1 inhibition to promote tumor regression in RBM10‐deficient tumors. Collectively, RBM10 serves as a key immunoregulator in LUAD by modulating the STING‐CCL7‐CCR2 axis, and targeting the CCL7‐CCR2 axis represents a promising strategy to overcome anti‐PD‐1 resistance.

Third‐generation epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR‐TKIs) are standard first‐line therapy for advanced, EGFR ‐mutated nonsmall cell lung cancer (NSCLC). However, their benefit is limited in patients who have co‐existing tumor suppressor gene (TSG) mutations, highlighting a need for intensified strategies to improve outcomes. ACROSS2 (ClinicalTrials.gov identifier NCT04500717) is the first prospective, multicenter, randomized phase 3 study to compare the third‐generation EGFR‐TKI aumolertinib in combination with carboplatin–pemetrexed versus aumolertinib monotherapy in patients who had NSCLC with EGFR mutations and concomitant TSG mutations. In total, 126 patients were enrolled and randomly assigned to either combination therapy ( n = 62) or monotherapy ( n = 64). The primary end point was median progression‐free survival (PFS). At a median follow‐up of 25.3 months, combination therapy significantly prolonged median PFS compared with monotherapy (19.78 vs 16.53 months; hazard ratio, 0.58; 95% confidence interval, 0.34–0.97). Landmark PFS rates at 12, 18, and 24 months were 78.7% versus 65.3%, 67.2% versus 40.8%, and 41.0% versus 29.9%, respectively. Subgroup analyses demonstrated a clear PFS benefit in patients who had co‐existing tumor protein p53 ( TP53 ) mutations. Grade 3 or greater adverse events occurred in 25.9% of patients who received combination therapy versus 17.2% of those who received monotherapy; no drug‐related deaths were observed. Overall survival data were immature (data maturity, 4%). The ACROSS2 trial provides the first prospective evidence supporting a genotype‐directed, chemotherapy‐targeted intensification approach favoring aumolertinib plus carboplatin–pemetrexed for this molecularly defined population.

The emergence of glycosylated RNA (GlycoRNA) has expanded the paradigm of macromolecular glycosylation beyond proteins and lipids, revealing previously unrecognized layers of regulation within glycoscience and RNA biology. Increasing evidence suggests that GlycoRNA contributes to immune recognition and tumor progression. However, its biological functions and translational potential remain insufficiently characterized. GlycoRNAs are predominantly derived from small non-coding RNAs and are decorated with sialylated and fucosylated N- or O-linked glycans. Processed through canonical glycosylation pathways, they are displayed on the cell surface and contribute to tumor–immune interactions. Sialylated GlycoRNAs can bind sialic acid-binding immunoglobulin-like lectins on immune cells, generating inhibitory signaling that facilitates immune escape. Conversely, partial removal of glycans exposes modified uridine structures such as acp³U, which can activate Toll-like receptor–mediated innate immunity, indicating a glycan-dependent dual regulatory mechanism. Beyond immune regulation, alterations in GlycoRNA abundance are also associated with cancer cell migration, invasion, and metabolic adaptation. In metabolically stressful microenvironments, such as brain metastases, enhanced glycolysis increases substrates, including UDP-GlcNAc, which may further drive GlycoRNA modification and cell-surface presentation, establishing a positive feedback loop linking metabolic reprogramming to immune regulation. Given their stability on tumor cells and in circulation, GlycoRNAs represent promising biomarkers for liquid biopsy and emerging targets for immunotherapy. A comprehensive understanding of GlycoRNA glycosylation, structural determinants, and immune interactions will be essential to guide the development of diagnostic and therapeutic strategies in cancer.

Concurrent or sequential chemoradiotherapy followed by immunotherapy (CCRT/SCRT→IO), known as the PACIFIC regimen, is the standard of care for unresectable, driver gene‐negative Stage III non‐small cell lung cancer (NSCLC). However, in real‐world practice, some patients cannot proceed to immunotherapy due to toxicity, declining performance status, or disease progression. This multicenter retrospective study included 960 patients from 14 Chinese institutions (2011–2023) to evaluate the efficacy and safety of alternative regimens. Patients were stratified into five groups. Primary endpoints were progression‐free survival (PFS) and overall survival (OS); secondary endpoints included objective response rate, disease control rate, duration of response, and immune‐related adverse events (irAEs). Inverse probability treatment weighting was used to adjust for baseline differences. Among 911 evaluable patients, weighted median PFS was 21.7 months for (IO + CCRT/SCRT) → IO, 16.8 for (IO + Chemo) → IO, 25.8 for CCRT/SCRT → IO, 7.1 for chemotherapy alone, and 14.8 for CCRT/SCRT. Median OS was not reached in the (IO + CCRT/SCRT) → IO group and ranged from 31.1 to 58.3 months in others. No significant differences in PFS or OS were found between (IO + CCRT/SCRT) → IO and CCRT/SCRT → IO. Pneumonitis occurred most frequently in the CCRT/SCRT → IO group. Early initiation of IO did not significantly increase irAE risk. These findings support early integration of IO with chemoradiotherapy and maintenance IO as a viable option for unresectable Stage III NSCLC.

Purpose:Tifcemalimab is a recombinant humanized IgG4k monoclonal antibody targeting B- and T-lymphocyte attenuator. Co-blockade of B- and T-lymphocyte attenuator and programmed death-1 pathways improved outcomes in nonclinical models. This phase I/II trial evaluated the safety and preliminary efficacy of tifcemalimab plus toripalimab in advanced lung cancer.Patients and Methods:Eligible patients with pathologically confirmed advanced non–small cell lung cancer (NSCLC) without sensitive EGFR variation and anaplastic lymphoma kinase fusion who failed standard treatment including one PD-1/PD-L1 inhibitor or those with refractory extensive-stage small cell lung cancer (SCLC) received tifcemalimab (200 mg) and toripalimab (240 mg) every 3 weeks intravenously until disease progression or intolerable toxicity. The Simon two-stage optimal design was used in the expansion part. The primary endpoints included safety and objective response rate (ORR) per RECIST version 1.1.Results:Twenty-four patients with NSCLC and 43 with SCLC were enrolled (median age of all patients, 60.0 years). All patients with NSCLC and 14 (32.6%) with SCLC had received previous immunotherapy. Fifty-five (82.1%) patients experienced treatment-related adverse events, and five (7.5%) patients reported grade ≥3 immune-related adverse events. For NSCLC, the ORR was 4.3%, and disease control rate was 47.8%. The median progression-free survival and overall survival were 1.5 and 18.9 months, respectively. For SCLC, the ORR and disease control rate were 35.0% and 55.0%, respectively. The median duration of response, progression-free survival, and overall survival were 5.7, 2.8, and 12.3 months, respectively.Conclusions:Tifcemalimab plus toripalimab showed promising antitumor activities with acceptable safety, especially in advanced refractory SCLC.

Supplementary Table 2. Representativeness of study participants.