Hao Long

Background: Neoadjuvant immunochemotherapy (nICT) is increasingly used for resectable non-small cell lung cancer (NSCLC), yet a substantial proportion of patients fail to achieve pathological complete response (pCR). Clinically scalable, minimally invasive biomarkers that predict response and point to actionable resistance mechanisms remain needed. Methods: Pretreatment plasma samples collected prior to the first dose were profiled using the Olink proximity extension assay in a Sun Yat-sen University Cancer Center cohort (n=86), randomly split into a training set (n=65) and an internal validation set (n=21). Differentially abundant proteins associated with pCR were identified, and predictive models were developed using logistic regression, random forest, and extreme gradient boosting (XGBoost), followed by internal validation and independent external validation in the Jiangmen Central Hospital cohort (n=46). Survival associations were evaluated by Cox regression. Mechanistic analyses integrated tumor immunohistochemistry/multiplex immunofluorescence, bulk RNA sequencing with immune deconvolution, and functional validation in subcutaneous and orthotopic murine lung cancer models with pharmacologic leukemia inhibitory factor (LIF) blockade. Results: Four candidate proteins (LIF, CXCL1, CX3CL1, and NT-3) showed modest single-marker discrimination for pCR (area under the curve (AUC), 0.611–0.673). Multiprotein models improved prediction, with XGBoost achieving the highest performance (training AUC=0.95; internal validation AUC=0.845 (95% CI 0.65 to 1.00); external validation AUC=0.801 (95% CI, 0.57 to 0.93)). SHapley Additive exPlanations analysis identified LIF as the dominant feature negatively associated with pCR probability. Elevated baseline plasma LIF was associated with inferior overall survival (HR=13.003; 95% CI 1.456 to 116.135; p=0.0217) and progression-free survival (HR=3.75; 95% CI 1.362 to 10.327; p=0.0105) after nICT. High LIF tumors exhibited reduced CD8 ⁺ T-cell infiltration and suppressed cytotoxic effector programs. In murine models, LIF blockade synergized with immunochemotherapy to enhance antitumor efficacy, restore CD8 ⁺ T-cell effector function, and mitigate T-cell exhaustion. Conclusions: Baseline plasma proteomics shows promise for predicting pCR to nICT in resectable NSCLC and nominates LIF as a predictive, prognostic, and therapeutic candidate mediator of resistance. These findings warrant prospective validation and further investigation of LIF-targeted combination strategies in the neoadjuvant setting.

Objective: Immunotherapy has emerged as a promising treatment for patients with pulmonary lymphoepithelioma carcinoma (PLEC). This study aimed to evaluate the efficacy and safety of neoadjuvant immunochemotherapy in patients with PLEC. Methods: Clinical stage IB‐III patients with PLEC who underwent neoadjuvant immunochemotherapy followed by radical surgery were retrospectively collected from two centers. For comparative analysis, 83 lung squamous cell carcinoma (LUSC) and 82 lung adenocarcinoma (LUAD) patients receiving the same neoadjuvant regimen were retrospectively enrolled. Pathological response and survival outcomes were compared between PLEC and the other cohorts. To minimize selection bias and potential confounding factors, the data were analyzed using inverse probability of treatment weighting (IPTW). Results: Among 40 patients with PLEC, 23 (57.5%) were female, with a mean age of 50.2 years. Major pathological response (MPR) was identified in 18 patients (45.0%) and pathological complete response (pCR) was achieved in 8 patients (20.0%). The median event‐free survival (EFS) was 24.8 months, with 1‐year and 2‐year EFS rates of 92.3% and 76.6%. Following IPTW adjustment, both pathological response and survival outcomes were comparable among the three cohorts. No statistically significant differences were observed between PLEC and LUSC patients in terms of MPR (45.0% vs. 66.3%, p = 0.306), pCR (20.0% vs. 47.0%, p = 0.228), or EFS (median: 24.8 vs. 28.5 months, p = 0.983). Similarly, PLEC demonstrated comparable MPR, pCR, and EFS to the LUAD cohort (MPR: 45.0% vs. 41.5%, p = 0.646; pCR: 20.0% vs. 25.6%, p = 0.978; median EFS: 24.8 vs. 22.5 months, p = 0.623). Conclusion: Neoadjuvant immunochemotherapy demonstrates favorable efficacy and safety in patients with PLEC in this retrospective two‐center cohort. In adjusted analyses, EFS did not significantly differ from that observed in matched LUSC or LUAD patients, suggesting that this approach may be a reasonable option for selected PLEC patients.

Background: Effective neoadjuvant immunochemotherapy (nICT) can downstage central-type non-small cell lung cancer (NSCLC) and reopen previously obstructed bronchi, but surgical decisions are frequently still anchored to pre-treatment staging. This study aimed to evaluate whether a standardized post-nICT restaging-guided surgical strategy could safely support surgical de-escalation while maintaining oncologic safety in selected patients with central-type NSCLC. Methods: We conducted a single-center retrospective cohort study of central-type NSCLC involving or abutting the lobar/main bronchus, initially considered to require at least sleeve resection or pneumonectomy. Patients with clinical stage I–III disease who received platinum-based nICT and subsequently showed radiologic partial response (PR)/complete response (CR) and no visible residual endobronchial tumor were included. Surgical management followed either a pre-nICT staging-guided surgery (TN-pre) or a post-nICT restaging-guided surgery (PRS), which linked specific post-nICT computed tomography (CT) and bronchoscopic criteria to de-escalation from pneumonectomy/sleeve resection to lobectomy when R0 resection was deemed feasible. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline imbalances. We compared pathologic response, margin status, perioperative outcomes, overall survival (OS), disease-free survival (DFS), and recurrence patterns. Results: A total of 122 patients were analyzed (78 PRS, 44 TN-pre). After IPTW, demographic and clinicopathologic features were well balanced. Post-neoadjuvant therapy pathologic tumor-node-metastasis (ypTNM) stage distribution, major pathological response (MPR) rates (83.6% vs. 70.7%; P=0.10), and R0 resection rates were comparable between PRS and TN-pre, with a trend toward fewer R1 margins in PRS (1.6% vs. 7.3%; P=0.07). PRS significantly reduced operative time, chest drainage duration, and intensive care unit (ICU) stay, while intraoperative blood loss, postoperative hospital stay, and 30-day mortality remained similar. No significant differences were observed in OS, DFS, or patterns of locoregional and distant recurrence. Conclusions: A post-treatment restaging-guided strategy that explicitly incorporates CT and bronchoscopic response allows safe de-escalation of surgery in selected central-type NSCLC after nICT, converting many planned pneumonectomies or sleeve resections to lobectomy. This response-adapted approach improves perioperative metrics without an early detrimental impact on oncologic outcomes. However, these survival findings should be considered hypothesis-generating and warrant further validation through long-term prospective studies.

Background: Neoadjuvant anti‐programmed cell death 1 (PD‐1) immunochemotherapy has shown promising efficiency in the treatment of early‐stage non‐small‐cell lung cancer (NSCLC), but it has not consistently yielded durable responses. Biomarkers for the prediction of efficacy are warranted. Methods: We performed shotgun metagenomic and plasma/faecal metabolomic studies in 44 NSCLC patients who underwent neoadjuvant tislelizumab plus platinum‐based doublet chemotherapy. Samples were collected at baseline and before surgical resection, and the major pathologic response (MPR) was evaluated. Results: MPR patients showed a significantly higher gut‐microbial alpha diversity, an enrichment of Ruminococcaceae , Lachnospiraceae and Clostridiales species, and an increased plasma level of tryptophan metabolites at baseline. On the contrary, non‐MPR patients were characterized by enrichment of Prevotella species in faecal samples and higher plasma levels of linoleic acid metabolites. A high predictive accuracy was achieved using a small panel of differential microbial ( Clostridium sp. M62/1 and Eisenbergiella tayi ) or metabolomic features (linoleic acid, oxindole‐3‐acetic acid and quinolinic acid) with AUCs > .85. Conclusions: The baseline characteristics of the gut microbiota and plasma metabolites could provide early predictions of the response to neoadjuvant anti‐PD‐1 immunochemotherapy. Trial registration: NCT05244837. Key points: Baseline metagenomic and metabolomic signatures were significantly associated with the major pathologic response of neoadjuvant anti‐PD‐1 immunochemotherapy. Integrated microbial model (consists of Clostridium sp. M62/1 and Eisenbergiella tayi ) and metabolomic model (consists of linoleic acid, oxindole‐3‐acetic acid and quinolinic acid) could provide early predictions of the response.

Pulmonary lymphoepithelioma carcinoma (PLEC), a rare non-small cell lung cancer subtype strongly associated with Epstein-Barr virus (EBV) infection, currently lacks a standardized treatment regimen. Conventional platinum-based systemic chemoradiotherapy remains the primary approach. In recent years, its distinctive pathological features and tumor immune microenvironment have established a compelling rationale for immune checkpoint inhibitors (ICIs). Clinical studies have demonstrated promising efficacy and acceptable safety of ICIs, both as monotherapy and in combination with chemotherapy, in patients with advanced and resectable PLEC. Neoadjuvant immunotherapy has also emerged as a viable strategy to downstage tumors and improve resectability in operable cases. However, the rarity of PLEC has limited the availability of large-scale prospective trials, and current evidence is predominantly derived from retrospective analyses. Key challenges, including predictive biomarkers, mechanisms of immunotherapy, and optimal combination strategies, remain to be addressed. This review systematically summarizes the current clinical evidence, molecular mechanisms, and immune microenvironment characteristics of PLEC, and discusses future research directions. .

The efficacy, safety and ideal treatment duration of an adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for patients with resected EGFR-mutated non-small-cell lung cancer (NSCLC) were not known until 2014, when this study was initiated. In this phase 3 ICTAN trial (GASTO1002, NCT01996098), patients with completely resected, EGFR-mutated, stage II-IIIA NSCLC after adjuvant chemotherapy were assigned in a 1:1:1 ratio to receive icotinib (125 mg, three times daily) for 12 months, to receive icotinib for 6 months, or to undergo observation. The primary endpoint was disease-free survival (DFS). This trial was terminated early. A total of 251 patients were randomized. Adjuvant icotinib for 12 months significantly improved DFS (hazard ratio [HR]: 0.40, 95% confidence interval [CI], 0.27–0.61; P < 0.001) and overall survival (OS; HR: 0.55, 95% CI, 0.32–0.96; P = 0.032) compared with observation. Adjuvant icotinib of 6 months also significantly improved DFS (HR: 0.41, 95% CI, 0.27–0.62; P < 0.001) and OS (HR: 0.56, 95% CI, 0.32–0.98; P = 0.038) compared with observation. Adjuvant icotinib for 12 months did not improve DFS (HR: 0.97; P = 0.89) or OS (HR: 1.00; P = 0.99) compared with 6 months of this drug. Rates of adverse events of grade 3 or higher were 8.3%, 6.0% and 2.4% for the 12-month icotinib, 6-month icotinib, and observation groups, respectively. Adjuvant icotinib for 12 months or 6 months following adjuvant chemotherapy improved DFS and OS compared with observation in patients with resected EGFR-mutated stage II-IIIA NSCLC with a manageable safety profile, supporting it as a potential treatment option.

Background: The previously reported primary analyses of NeoTAP01 trial demonstrated encouraging effectiveness and safety of perioperative toripalimab plus chemotherapy in resectable stage III non-small cell lung cancer (NSCLC). We now present the 4-year follow-up outcomes in order to confirm the stability of its benefits. Methods: This trial enrolled 33 NSCLC patients with resectable IIIA and IIIB to receive three cycles of neoadjuvant toripalimab plus chemotherapy before surgery. Adjuvant toripalimab was suggested to conduct for 12 cycles postoperatively. With a median follow-up of 4.3 years, long-term outcomes, including event-free survival (EFS), overall survival (OS), and treatment-related adverse effects (TRAEs) were reported. Post hoc analyses explored the risk factors of recurrence in the level of pathologic and genomic characteristics. Results: In the per-protocol (PP) population, 4-year EFS and OS rates were 66.7% and 83.3%, respectively. The presence of pathologic complete response (pCR) trended toward favorable EFS [4-year EFS, 92.9% vs. 46.7%; hazard ratio (HR), 0.09; 95% confidence interval (CI): 0.01 to 0.76]. All the patients with recurrence in the non-pCR subgroup had received adjuvant treatment, and 75% of them experienced recurrence in less than 1 year after surgery. For the TRAEs, grade 3 pneumonitis happened in 11.1% (3/27) patients during the adjuvant therapy. STK11 and KEAP1 mutations were not associated with long-term survival risks. Conclusions: The 4-year clinical outcomes for perioperative toripalimab plus chemotherapy in resectable stage III NSCLC showed a sustained improvement in long-term EFS and OS. However, the effectiveness of adjuvant immunotherapy are still unclear, as definitive conclusions are limited by cohort size.

Background: Lymph nodes are crucial for perioperative immunotherapy but have to be completely resected in surgery. Trials evaluating the safety and necessity of omitting systemic mediastinal lymph node (mLN) dissection in non-small cell lung cancer (NSCLC) are still absent.Methods: cN0/N1 NSCLC patients who received neoadjuvant immunotherapy and radical surgery were retrospectively collected from three institutions. Restricted cubic spline regression and receiver operating characteristic curve were used to analyze the association between mLN dissection number and survival outcomes. Confounding factors between selective and systemic mLN dissection groups were adjusted by inverse probability of treatment weighting (IPTW). The characteristics of memory CD8⁺ T cells in immunotherapy-treated mLN were identified by single-cell RNA and T-cell receptor sequencing (scRNA/TCR-seq) data retrieved from GSE185206.Results: From 2019 to 2021, 131 neoadjuvant-treated cN0/N1 NSCLC patients were collected. The mLN clearance rate was 98.5% in the whole cohort and 100% in patients with radiologically confirmed complete response. Resected lymph node counts were irrelevant with local recurrence, distant metastasis, or death. Compared with selective mLN dissection, systemic mLN dissection did not show any survival benefit but showed slightly higher postoperative recurrence risk in both unadjusted and IPTW-adjusted cohorts. scRNA/TCR-seq showed that stem-like exhausted CD8⁺ memory T cells were the progenitors of tumor-specific CD8⁺ T lymphocytes in primary tumors and were abundantly enriched in resected mLN.Conclusions: Omitting systemic mLN dissection was safe in cN0/N1 NSCLC patients who received neoadjuvant immunotherapy. Excessive mLN dissection may disrupt the repertoire of stem-like exhausted CD8⁺ memory T cells and consequently impair the efficacy of adjuvant immunotherapy.

Background: The use of programmed death-1 (PD-1) inhibitors in the neoadjuvant setting for patients with resectable stage III NSCLC has revolutionized this field in recent years. However, there is still 40%-60% of patients do not benefit from this approach. The complex interactions between immune cell subtypes and tertiary lymphoid structures (TLSs) within the tumor microenvironment (TME) may influence prognosis and the response to immunochemotherapy. This study aims to assess the relationship between immune cells subtypes and TLSs to better understand their impact on immunotherapy response.Methods: This study initially compared the tertiary lymphoid structures (TLSs) density among patients who underwent immunochemotherapy, chemotherapy and upfront surgery using 123 tumor samples from stage-matched patients. Multiplex immunohistochemistry (mIHC) was employed to analyze the spatial distribution of PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs. Cytometry by time-of-flight (CyTOF) was used to assess immune cell dynamics in paired biopsy and resection specimens from six patients who underwent immunochemotherapy. Key immune cells were validated in newly collected samples using flow cytometry, mIHC, and in vitro CAR-T cells model.Results: Patients who underwent neoadjuvant chemotherapy or immunochemotherapy exhibited increased TLSs compared to those who opted for upfront surgery. The TLS area-to-tumor area ratio distinguished pCR+MPR and NR patients in the immunochemotherapy group. Spatial analysis revealed variations in the distance between PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs in the immunochemotherapy group. CyTOF analysis revealed an increase in the frequency of key immune cells (CCR7+CD127+CD69+CD4+ and CD38+CD8+ cells) following combined therapy. Treatment responders exhibited an increase in CCR7+CD4+ T cells, whereas CD38+CD8+ T cells were associated with compromised treatment effectiveness.Conclusions: Immunochemotherapy and chemotherapy increase TLSs and granzyme B+ CD8+ T cells in tumors. The TLS area-to-tumor ratio distinguishes responders from non-responders, with PD-L1+ dendritic cells near CD8+PD-1+ T cells linked to efficacy, suggesting that PD-1 inhibitors disrupt harmful interactions. Post-immunochemotherapy, CD8+ T cells increase, but CD38+CD8+ T cells show reduced functionality. These findings highlight the complex immune dynamics and their implications for NSCLC treatment.