The identification of reliable biomarkers is crucial for enhancing prognostic assessments and therapeutic strategies in lung cancer. A study employing a whole-genome, tumor-informed circulating tumor DNA (ctDNA) detection approach analyzed 2,994 plasma samples from 431 patients with non-small cell lung cancer (NSCLC). The findings revealed that ultrasensitive ctDNA detection, with a threshold below 80 parts per million, is highly prognostic, particularly when combining pre- and postoperative ctDNA statuses to identify an intermediate risk group, thereby improving disease stratification (ref: Black doi.org/10.1016/j.cell.2025.10.020/). Additionally, a randomized phase 2 trial demonstrated that local consolidative therapy (LCT) combined with immunotherapy significantly enhances survival in NSCLC patients with oligo-residual disease after anti-PD-1/L1 therapy. The study highlighted that cryoablation may offer superior survival benefits compared to thermal ablation (ref: Yang doi.org/10.1038/s41392-025-02460-z/). Furthermore, research into small cell lung cancer (SCLC) revealed that spatial proteomic profiling can uncover conserved prognostic immune microenvironment features across molecular subtypes, although these features showed limited prognostic power (ref: Zhai doi.org/10.1016/j.phrs.2025.108048/).

The mechanisms underlying resistance to immunotherapy in lung cancer are complex and multifaceted. A study identified MUC1 as a key player in conferring inflammatory memory of tyrosine kinase inhibitor (TKI) resistance in NSCLC, suggesting that targeting MUC1-C with an antibody-drug conjugate could be a viable therapeutic strategy for TKI-refractory cases (ref: Takamori doi.org/10.1038/s41392-025-02482-7/). In a separate case report, the concurrent use of alectinib and chemotherapy during pregnancy in a patient with ALK-rearranged NSCLC was documented, emphasizing the need for careful management in such complex scenarios (ref: Pham doi.org/10.1016/j.jtho.2025.11.012/). Additionally, the transcription factor POU2F3 was found to be critical for tuft cell identity in SCLC, and its suppression led to tumor regression in xenograft models, highlighting potential therapeutic targets (ref: Alpsoy doi.org/10.1016/j.celrep.2025.116572/).

Targeted therapies continue to evolve in the treatment of NSCLC, particularly for patients with specific genetic alterations. The phase 2 KANNON study demonstrated that andamertinib, a targeted therapy for EGFR exon 20 insertions, achieved a confirmed overall response rate of 42.7% in patients previously treated with platinum-based chemotherapy or immunotherapy, indicating its potential as a viable option in this challenging cohort (ref: Yang doi.org/10.1016/j.jtho.2025.11.008/). Similarly, lorlatinib showed durable efficacy in TKI-naive advanced ROS1-positive NSCLC, reinforcing its role in earlier treatment settings (ref: Ahn doi.org/10.1001/jamaoncol.2025.5097/). Furthermore, a prospective phase II study combining bevacizumab with fractionated stereotactic radiotherapy for extensive brain metastases in NSCLC patients indicated promising efficacy, suggesting a synergistic approach to treatment (ref: Zhou doi.org/10.1002/cac2.70078/).

The tumor microenvironment (TME) plays a pivotal role in modulating immune responses in lung cancer. A study on neoadjuvant immune checkpoint blockade (NA-ICB) revealed that CD8+CX3CR1+ T cells were significantly enriched in responsive tumors, indicating their potential as biomarkers for treatment efficacy (ref: Dai doi.org/10.1038/s41416-025-03160-9/). Additionally, GPX4-deficient tumor cells were shown to evade ferroptosis and impair antitumor immunity by reprogramming lipid metabolism, suggesting that targeting this pathway could enhance therapeutic responses (ref: Wang doi.org/10.1093/procel/). Moreover, the role of USP22 in immune evasion and resistance to checkpoint blockade was highlighted, positioning it as a potential therapeutic target to overcome resistance mechanisms (ref: Liu doi.org/10.1172/JCI193162/).

Genomic alterations significantly influence cancer progression and treatment responses in NSCLC. A study examining MTAP deletions found that these alterations often co-occur with oncogenic driver mutations, and patients with MTAP deletions responded favorably to PRMT5 inhibitor therapy, suggesting a potential therapeutic strategy for this subset (ref: Ross doi.org/10.1016/j.jtho.2025.11.010/). Additionally, research on GLMP revealed its role in promoting EGFR-TKI resistance through the activation of autophagy and the RhoA pathway, indicating that dual-targeting strategies may be necessary to combat resistance (ref: Liang doi.org/10.1038/s41698-025-01135-w/). Furthermore, the development of TMBclaw, a novel graph learning approach, aims to improve immunotherapy response predictions by accounting for tumor clonal heterogeneity, addressing a significant challenge in current prognostic methodologies (ref: Wang doi.org/10.1093/bib/).

Clinical trials remain essential for evaluating new treatment strategies in lung cancer. The EVOKE-02 study demonstrated that the combination of sacituzumab govitecan and pembrolizumab yielded an overall response rate of 66.7% in patients with metastatic NSCLC, particularly benefiting those with high PD-L1 expression (ref: Reck doi.org/10.1016/j.jtho.2025.10.016/). Additionally, a multicenter retrospective study assessed the prognostic value of the Lung Immune Prognostic Index (LIPI) in patients with PD-L1-low/negative tumors receiving chemoimmunotherapy, highlighting its potential to guide treatment decisions in this challenging subgroup (ref: Yoshimura doi.org/10.1016/j.esmoop.2025.105906/). Furthermore, enozertinib was identified as a promising brain-penetrant EGFR inhibitor for treating NSCLC with atypical mutations, addressing a critical unmet need in this patient population (ref: Junttila doi.org/10.1158/0008-5472.CAN-25-3502/).

Research into neuroendocrine tumors, particularly small cell lung cancer (SCLC), has revealed significant insights into tumor biology and treatment options. A study utilizing single-cell RNA sequencing identified the cell of origin for small-intestinal neuroendocrine tumors, providing a clearer understanding of early tumor development (ref: Sei doi.org/10.1016/j.celrep.2025.116500/). In the context of SCLC, a phase II trial evaluated the efficacy of tislelizumab combined with anlotinib and irinotecan as second-line therapy, demonstrating promising results and manageable toxicity in patients who had previously undergone platinum-based chemotherapy (ref: Chen doi.org/10.1016/j.eclinm.2025.103502/). Additionally, spatial proteomic profiling in SCLC highlighted the immune microenvironment's complexity, revealing conserved features across molecular subtypes but limited prognostic power (ref: Zhai doi.org/10.1016/j.phrs.2025.108048/).

Innovative therapeutic strategies are emerging to address the challenges faced in treating non-small cell lung cancer (NSCLC). One study explored the use of proteolysis-targeting chimeras (PROTACs) to target CD26, a promising approach for patients with driver-negative NSCLC who lack effective treatments (ref: Zhang doi.org/10.1016/j.ebiom.2025.106026/). Additionally, the dynamic monitoring of plasma cell-free DNA methylation was investigated as a predictive biomarker for pathological response in resectable stage IIB-IIIB NSCLC, suggesting its utility in guiding neoadjuvant therapy decisions (ref: Liu doi.org/10.1186/s12916-025-04419-x/). Furthermore, the role of Plasminogen Activator Inhibitor-1 (PAI-1) in mediating tolerance to anti-PD-1 immunotherapy was highlighted, indicating that targeting PAI-1 may enhance the efficacy of immune checkpoint inhibitors (ref: Sumii doi.org/10.1158/1535-7163.MCT-24-0890/).