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Published on: April 22, 2019
Neoadjuvant Immunochemotherapy in Resectable NSCLC With SMARCA4 Alterations
Li-Shan Peng1, Qian Cui2, Chao Zhang1
1Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer, Guangzhou, China.
Introduction:
Neoadjuvant immunochemotherapy has improved pathologic complete response (pCR) rates and event-free survival in resectable NSCLC, yet its efficacy in SMARCA4-altered NSCLC, a subset associated with poor prognosis, remains unclear.
Methods:
We retrospectively analyzed clinical characteristic and next-generation sequencing of 29 patients with SMARCA4-altered NSCLC who received neoadjuvant immunochemotherapy from Guangdong Provincial People's Hospital. The Cancer Genome Atlas of lung adenocarcinoma was classified through SMARCA4 condition by whole exome sequencing and further analyzed the difference between the two groups. In the altered group, BostonGene molecular functional portraits were used for tumor immune microenvironment classification.
Results:
In general, 29 NSCLC patients with SMARCA4 alterations received neoadjuvant immunochemotherapy, the objective response rate was 70.4%, and the pCR rate was 51.7%. The pCR rate significantly differed among pathologic subgroups (squamous cell carcinoma [SCC] versus adenocarcinoma, 83.3% versus 28.6%, p = 0.045). After a median follow-up of 17 months, seven patients relapsed and one died from non-cancer causes. In adenocarcinoma subgroup, SMARCA4 alterations were associated with early progression (42.8%) with a median event-free survival of 13 months, although some patients achieved durable survival. All patients harboring co-occurring KRAS with KEAP1/STK11 mutations relapsed. The Cancer Genome Atlas data revealed that patients with SMARCA4-altered lung adenocarcinoma had worse survival (34.8 versus 50.9 mo, p = 0.033), down-regulation in innate immunity, and enrichment of mTOR/MYC signaling. Immune classification revealed both immune-desert and immune-enriched subtypes within the altered cohort. The lacking immune cell infiltration group had significantly shorter overall survival compared with the immune-enriched subtypes (28.8 versus 49.9 mo, p = 0.043).
Conclusions:
In conclusion, SMARCA4-altered NSCLC is heterogeneous. SCC demonstrates remarkable sensitivity with immunochemotherapy, but non-SCC, especially with KRAS+KEAP1/STK11 co-mutations, represents a distinct, immune-cold, high-risk subtype.
Insights
Neoadjuvant immunochemotherapy shows promise in SMARCA4-altered non-small cell lung cancer (NSCLC), particularly in squamous cell carcinoma. However, other subtypes, especially those with KRAS mutations, present a distinct immune-cold, high-risk profile.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Neoadjuvant immunochemotherapy improves outcomes in non-small cell lung cancer (NSCLC).
- The efficacy of this treatment in SMARCA4-altered NSCLC, a poor-prognosis subset, is not well understood.
- SMARCA4 alterations are associated with aggressive disease and poorer survival in lung adenocarcinoma.
Purpose of the Study:
- To evaluate the efficacy of neoadjuvant immunochemotherapy in patients with SMARCA4-altered NSCLC.
- To investigate the clinical characteristics and tumor immune microenvironment of SMARCA4-altered NSCLC.
- To identify factors associated with treatment response and survival in this patient population.
Main Methods:
- Retrospective analysis of 29 patients with SMARCA4-altered NSCLC treated with neoadjuvant immunochemotherapy.
- Next-generation sequencing for comprehensive genomic profiling.
- Analysis of tumor immune microenvironment using molecular functional portraits.
- Comparison with The Cancer Genome Atlas (TCGA) data for lung adenocarcinoma.
Main Results:
- Objective response rate of 70.4% and pathologic complete response (pCR) rate of 51.7% in the overall cohort.
- Significantly higher pCR rates in squamous cell carcinoma (83.3%) compared to adenocarcinoma (28.6%).
- SMARCA4-altered lung adenocarcinoma showed worse survival and immune-cold characteristics, with KRAS/KEAP1/STK11 co-mutations predicting early relapse.
Conclusions:
- SMARCA4-altered NSCLC is a heterogeneous disease with varying responses to immunochemotherapy.
- Squamous cell carcinoma demonstrates high sensitivity to neoadjuvant immunochemotherapy.
- Non-squamous subtypes, particularly those with KRAS and KEAP1/STK11 co-mutations, represent an immune-cold, high-risk subgroup requiring distinct therapeutic strategies.
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