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Background Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. Methods We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). Results Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. Conclusions Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.

Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor ( EGFR )-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment. Afatinib is a second-generation EGFR tyrosine kinase inhibitor recommended as the first-line treatment for patients with advanced EGFR mutant non-small cell lung cancer (NSCLC). Here the authors report the results of a phase II clinical trial of neoadjuvant afatinib for stage III EGFR mutant NSCLC.

Introduction: Neoadjuvant immunochemo-therapy (nICT) has been recommended as the standard regimen for locally advanced non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGA). However, the efficacy of nICT for patients harbing human epidermal growth factor receptor 2 (HER2) mutation remains uncertain. Here, we report two locally advanced HER2-mutant NSCLC received nICT followed by radical surgery. Case Presentation: This study reports two cases of patients with resectable HER2-mutant NSCLC in stage III. Both patients were 67-year-old males who received nICT followed by radical surgery. Postoperative pathological evaluation confirmed pathological complete response (pCR) in both patients. As of the last follow-up in June 30th, 2025, neither patient had evidence of disease recurrence, with disease-free survival (DFS) exceeding 36 months in both cases, demonstrating favorable therapeutic response and sustained outcomes. Conclusion: NICT for locally advanced NSCLC harboring HER2 mutations demonstrated promising efficacy and safety. These cases may be suggestive of the wider applicability of nICT in the perioperative management of this molecularly defined NSCLC subset.

Background This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II–III non-small-cell lung cancer (NSCLC). Methods Patient eligibility mainly involved treatment-naive, clinical stage II–III and wild-type EGFR/ALK NSCLC. The patients received 2–4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. Results In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS ( P =0.017) and PFS ( P =0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). Conclusions Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II–III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. Trial registration ChiCTR1900024014, June 22, 2019.

The efficacy and safety of induction-immunotherapy followed by surgery for unresectable Stage III non-small cell lung cancer (NSCLC) remain challenging. In this open-label, single-center, phase II clinical umbrella trial (ChiCTR2000035367), 100 unresectable Stage III NSCLC patients are enrolled. Patients with PD-L1 expression ≥ 50% but contraindications to anti-angiogenic therapy receive immuno-monotherapy. Patients with PD-L1 expression ≥ 1% and no contraindications to anti-angiogenic therapy receive immunotherapy plus anti-angiogenesis therapy. Patients with PD-L1 expression between 1% and 49%, contraindications to anti-angiogenic therapy, or negative/unknown PD-L1 expression receive chemoimmunotherapy. The primary endpoint is the major pathological response (MPR) rate. Among 47 surgically-treated patients, the MPR rate is 61.7% (95% confidence interval [CI]: 46.4%-75.5%), achieving the prespecified endpoint. For secondary endpoints, the objective response rate for all patients is 54.0% (95% CI: 43.7-64.0). The median event-free survival is 29.9 months (95% CI: 17.0-42.7). Most common adverse event is anemia (49.0%). Exploratory transcriptomic analyses reveal Bone Marrow Stromal Cell Antigen 1 (BST1) as a promising biomarker for response to chemoimmunotherapy. Generally, for unresectable stage III NSCLC patients, anti-PD1 based induction-therapy according to PD-L1 expression and contraindication to antiangiogenic therapy followed by surgery is a feasible option. Induction-immunotherapy before surgery has been suggested for patients with unresectable stage III non-small cell lung cancer (NSCLC). Here, the authors report a phase 2 umbrella clinical trial where patients with unresectable stage III NSCLC receive anti-PD1-based induction-therapy based on PD-L1 expression and contraindications to antiangiogenic therapy.

Aumolertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor ( EGFR -TKI), is widely utilized for advanced EGFR -mutant non-small cell lung cancer patients (NSCLCm). This single-arm, phase II trial (NCT04685070) assessed the feasibility of neoadjuvant Aumolertinib for unresectable stage III NSCLCm. Fifty-six patients were enrolled, with 51 participants receiving neoadjuvant Aumolertinib (110 mg/day, orally) and forming the intention-to-treat population. The primary endpoint was objective response rate (ORR). Secondary endpoints included major pathological response (MPR) rate, pathological complete response (pCR) rate, complete (R0) resection rate, event-free survival (EFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ORR was 70.6% (95% confidence interval: 58%-84%), meeting the pre-specified primary endpoint. Additionally, twenty-three (45.1%) participants converted into resectable disease and underwent surgery. Among them, R0 resection, MPR and pCR rates were 100%, 21.7%, and 13.0%, respectively. The median EFS and OS were not reached. While, the 1- and 2-year EFS rates were 88.2% and 58.8%, respectively. Fatigue (49.0%), alanine aminotransferase concentration elevation (39.2%), and rash (35.3%) were the most common treatment-related adverse events (TRAEs). Grade 3/4 TRAEs occurred in 5 patients (9.8%), and no grade 5 TRAE was recorded. RNA-sequencing based analysis revealed increased infiltration of CD8 + T-cells in post-treatment tumors compared to baseline, particularly in responsive and Ex19-Del mutation tumors. Collectively, neoadjuvant Aumolertinib showed promising efficacy and a surgical conversion rate with a tolerable safety profile for unresecable NSCLCm in stage III, potentially involved in the remodeling of tumor microenvironment. Aumolertinib is a third generation EGFR tyrosine kinase inhibitors, approved for use in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). Here, the authors report a phase 2 clinical trial investigating neoadjuvant aumolertinib in patients with unresectable stage III EGFR-mutant NSCLC.

Background In small cell lung cancer (SCLC), the pathological N category is identical to it in non-small cell lung cancer (NSCLC) and remains unchanged over a decade. Here we verified the discriminability of number of involved nodal stations (nS) in SCLC and compared its efficacy in predicting survival with currently used pathological nodal (pN) staging. Methods We retrospectively analyzed the patients who received operations and were pathologically diagnosed as SCLC at Shanghai Pulmonary Hospital between 2009 and 2019. X-tile software was adopted to determine optimal cut-off values for nS groups. Kaplan–Meier method and Cox regression analysis were used to compare survival between different groups. Decision curve analysis (DCA) was employed to evaluate the standardized net benefit. Results A total of 369 patients were included. The median number of sampled stations was 6 (range 3–11), and the median number of positive stations was 1 (range 0–7). The optimal cutoff for nS groups was: nS0 (no station involved), nS1-2 (one or two stations involved), and nS ≥ 3 (three or more stations involved). Overall survival (OS) and relapse-free survival (RFS) were statistically different among all adjacent categories within the nS classification ( p  < 0.001, for both OS and RFS between each two subgroups), but survival curves for subgroups in pN overlapped (OS, p  = 0.067; RFS, p  = 0.068, pN2 vs. pN1). After adjusting for other confounders, nS was a prognostic indicator for OS and RFS. The DCA revealed that nS had improved predictive capability than pN. Conclusions Our cohort study demonstrated that the nS might serve as a superior indicator to predict survival than pN in SCLC and was worth considering in the future definition of the N category.

Background This study aimed to evaluate the efficacy and safety of camrelizumab, an anti-PD-1 antibody, combined with either chemotherapy or apatinib, a VEGFR-2 inhibitor, as neoadjuvant treatment for stage IIA–IIIA NSCLC. Methods This prospective, multicenter, dual-arm, non-randomized phase II trial enrolled participants from four hospitals in China between September 2020 and March 2022. Patients received 2–4 cycles of neoadjuvant treatment followed by surgery. Arm-AR ( n  = 28) included patients treated with camrelizumab (200 mg every 3 weeks) plus platinum-based chemotherapy, regardless of PD-L1 status. Arm-BR ( n  = 10) included PD-L1-positive patients treated with camrelizumab (200 mg every 3 weeks) plus apatinib (250 mg daily). The primary endpoint was the major pathological response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, objective response rate (ORR), disease control rate (DCR), event-free survival (EFS), overall survival (OS), and safety profiles. Results In the ITT population, MPR rates were 25.0% (95% CI 10.7–44.9) in arm-AR and 60.0% (95% CI 26.2–87.8) in arm-BR. The 24-month EFS rates were 53.6% and 70.0%, respectively, after a median follow-up of 30.5 months. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 25% of arm-AR patients and 10% of arm-BR patients. Conclusions Camrelizumab combined with platinum-based chemotherapy demonstrated promising efficacy and tolerability for resectable IIA–IIIA NSCLC, regardless of PD-L1 status. In PD-L1-positive patients, camrelizumab plus apatinib showed improved safety and effectiveness, highlighting a potential treatment option for this subgroup. Trial registration. NCT04379739, initiated on July 26, 2020.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significant benefits to patients with non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations; however, acquired resistance limits their long-term efficacy. Therefore, it remains an urgent requirement to discover the underlying mechanisms and investigate novel therapeutic strategies for overcoming the resistance to EGFR TKIs. The present study aimed to determine the mechanism underlying the resistance of NSCLC cells to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, the osimertinib-resistant NSCLC cell sub-line HCC827/OR was established in the present study. It was found that the expression levels of Bcl-2 and Bcl-xL were significantly upregulated in resistant cells compared with sensitive cells. Furthermore, the suppression of Bcl-2 and Bcl-xL through small interfering RNA-mediated gene knockdown or using a small molecule specific inhibitor ABT-263 re-sensitized HCC827/OR cells to osimertinib treatment. Moreover, the combined treatment of HCC827/OR cells with ABT-263 and osimertinib enhanced the rate of cell apoptosis through the mitochondrial apoptotic pathway. Finally, ABT-263 was able to overcome the resistance of osimertinib in xenograft tumor models. In conclusion, these findings may provide an improved concept for the development of a novel combined therapeutic strategy for the treatment of NSCLC resistance to EGFR TKIs.

ObjectiveLung adenosquamous carcinoma (ASC) is a rare histological subtype of non-small cell lung cancer (NSCLC). Due to its rarity, the studies about 18F-FDG PET/CT in this kind of pulmonary tumor were quite limited. Thus, this study investigated 18F-FDG PET/CT findings in ASC and its correlation with clinicopathological features and clinical outcomes.MethodsPreoperative 18F-FDG PET/CT findings and parameters of maximum standard uptake value (SUVmax), metabolic tumor volume and total lesion glycolysis of primary lesion (MTV-P, TLG-P), combination of primary lesion and metastases (MTV-C, TLG-C), and clinicopathological features were retrospectively investigated in patients with ASC. Moreover, progression-free survival (PFS) was also analyzed.ResultsAll 41 patients (25 men; 16 women; age: 60 ± 7 years) had single ASC with the mean diameter of 33 ± 14 mm. Six lesions were located centrally and 35 peripherally. Serum tumor markers were abnormally increased sporadically. Twenty-two cases were at TNM stage I, 9 at II, and 10 at III. The primary tumors were FDG-avid in all cases, with the average SUVmax of 11.5 ± 6.0. SUVmax was significantly associated with tumor location, size, and TNM stage (P < 0.05). Forty-one lesions were subgrouped into 23 AC-predominant and 18 SCC-predominant lesions, and significant differences were observed for age, tumor size, and SUVmax in two groups (P < 0.05). The median PFS of 41 cases was 19 months, and 12-month and 24-month PFS rates were 72.1% and 36.1%, respectively. SUVmax, MTV-P, and TLG-C were significantly associated with PFS (P < 0.05).ConclusionsASC of the lung displayed high SUVmax on 18F-FDG PET/CT, which was associated with tumor location, size, TNM stage, and predominant histologic component. Moreover, metabolic parameters of 18F-FDG PET/CT were independent prognostic factors of this rare lung malignancy.