Induction of complete pathological response by immunochemotherapy in stage IIIA–N2 patients with SMARCA4-deficient lung adenocarcinoma: a case report

Introduction

Background

SMARCA4-deficient lung adenocarcinoma (SMARCA4-dADC) is a rare, highly aggressive non-small cell lung cancer (NSCLC) subtype (~10% of cases) characterized by SMARCA4 loss-of-function mutations or deletions (1). This disrupts chromatin remodeling, driving poor differentiation, malignant progression, and metastasis (2). Clinically, SMARCA4-dADC lacks common driver mutations, responds poorly to conventional chemotherapy, and carries a poor prognosis (3-5). The tumors also exhibit an immunosuppressive microenvironment, with reduced dendritic and CD4⁺ T cell infiltration and enrichment of fibroblast activation protein-α (FAP)⁺ fibroblasts and secreted phosphoprotein 1 (SPP1)⁺ macrophages, contributing to limited efficacy of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors (4,6,7).

Rationale and knowledge gap

Neoadjuvant chemoimmunotherapy has shown favorable tumor downstaging and improved resectability in several NSCLC subtypes; however, its efficacy in SSMARCA4-dADC remains largely unknown (8-10). Current evidence is limited to sporadic case reports, and robust clinical data supporting the safety and effectiveness of neoadjuvant chemoimmunotherapy in locally advanced SMARCA4-dADC are lacking, representing a significant knowledge gap (11,12).

Objective

This study aims to report a case of stage IIIA–N2 SMARCA4-dADC achieving pathological complete response (pCR) after neoadjuvant immunochemotherapy, and to explore the potential therapeutic value of this strategy in this aggressive tumor subtype. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-332/rc).

Case presentation

The patient, a 65-year-old male with a significant history of heavy smoking and chronic obstructive pulmonary disease, presented to our hospital in February 2025 with hemoptysis persisting for over 10 days. Laboratory evaluations revealed elevated tumor markers, including squamous cell carcinoma-related antigen, cytokeratin 19 fragment, carcinoembryonic antigen, carbohydrate antigen 24-2 (CA24-2), and neuron-specific enolase. Positron emission tomography-computed tomography demonstrated a hypermetabolic lesion in the upper lobe of the right lung, measuring approximately 6.1 cm × 5.8 cm × 4.0 cm, with a maximum standardized uptake value (SUVmax) of 16.5. This lesion was associated with pleural involvement and distal obstructive changes, as well as multiple lymph node metastases in the mediastinal 4R region, right hilar area 10, and right lung lobe 11 zone, with a short diameter of 1.2 cm and an SUVmax of 5.1. Bronchoscopic pathological examination revealed poorly differentiated adenocarcinoma, and immunohistochemical analysis indicated the following results: pan-cytokeratin (CKpan) positive, thyroid transcription factor-1 (TTF-1) negative, cytokeratin 7 (CK7) positive, Napsin A negative, p40 negative, CD56 negative, Ki-67 at 40%, and SMARCA4 negative (expression loss), with PD-L1 tumor cell expression less than 1% (Figure 1). Following a multidisciplinary team evaluation, which included thoracic surgery, medical oncology, pathology, and radiotherapy, the patient was diagnosed with non-small cell adenocarcinoma exhibiting SMARCA4 loss. The initial clinical stage was determined to be cT3N2aM0, stage IIIA, indicating a borderline resectable stage III lung cancer. It was decided to pursue induction therapy combining immunotherapy and chemotherapy, with the aim of downstaging the tumor to facilitate potential radical surgery. The patient subsequently underwent four cycles of induction therapy with the following regimen: albumin-bound paclitaxel at 125 mg/m² on days 1 and 5, carboplatin at a target area under the curve (AUC) of 5 on day 1, and tislelizumab at 200 mg on day 3. The patient did not experience significant drug-related adverse effects during the treatment. Post-treatment assessments revealed a marked reduction in the size of the primary tumor and lymph nodes (Figure 2), and the response was classified as a partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST). The disease was re-staged as ycT2aN0M0, stage IB. In June 2025, the patient is scheduled to undergo thoracoscopic right upper lobectomy and systematic lymph node dissection at our hospital. Following surgery, a systematic evaluation of the primary lesion and lymph nodes was conducted, revealing an absence of viable tumor cells and no evidence of metastatic tumor lesions in the lymph nodes submitted for examination. pCR, defined as ypT0N0, was achieved, with no viable tumor cells detected in the resected primary tumor or regional lymph nodes. Histopathological analysis showed that the specimen consisted of 0% viable tumor cells, 90% stromal cells, and 10% necrosis (Figure 3). The patient has been followed for 8 months after surgery and remains disease-free. Longer-term follow-up is ongoing. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Publication of this case report and accompanying images was waived from patient consent according to the Ethics Committee of Peking University People’s Hospital (Qingdao Hospital) review board (approval No. 2025PHDQB025-01).

Figure 1 Pre-treatment pathological and HE staining (magnification ×20). HE, hematoxylin and eosin.

Figure 2 Chest CT scans illustrating the patient’s treatment progression. (A) Prior to the initiation of neoadjuvant therapy, the lesion measured 66 mm by 53 mm. (B) Following two cycles of neoadjuvant therapy, the lesion size reduced to 46 mm by 41 mm, indicating a PR in efficacy evaluation. (C) After four cycles of neoadjuvant therapy, the lesion further decreased to 35 mm by 28 mm, with the efficacy evaluation indicating stable disease. (D) Immediately preceding surgical intervention, the lesion measured 31 mm by 28 mm. CT, computed tomography; PR, partial response.

Figure 3 After surgery pathological and HE staining (magnification ×10). HE, hematoxylin and eosin.

Discussion

Key findings

In this report, we describe a rare case of locally advanced SMARCA4-dADC that achieved a pCR following neoadjuvant chemoimmunotherapy and subsequent surgical resection. Treatment with tislelizumab combined with albumin-bound paclitaxel and carboplatin resulted in significant tumor regression, clinical downstaging, and successful R0 resection without perioperative complications. To our knowledge, this represents one of the few reported cases demonstrating pCR after neoadjuvant chemoimmunotherapy in SMARCA4-dADC, highlighting the potential efficacy of this approach in a tumor subtype traditionally associated with poor outcomes (11,13).

Strengths and limitations

The strength of this case lies in the pathological confirmation of pCR in both the primary tumor and lymph nodes, providing clear evidence of treatment efficacy. The neoadjuvant regimen was well tolerated, with no surgical delay or significant adverse events, supporting its feasibility. However, the single-case design and short follow-up limit the generalizability of the findings and preclude conclusions regarding long-term survival. Larger prospective studies are warranted.

Comparison with similar researches

Previous studies have shown that SMARCA4-dADC responds poorly to conventional chemotherapy, with response rates below 15% and short durations of response (14). Immune checkpoint inhibitors (ICIs), particularly PD-1 inhibitors, have demonstrated therapeutic potential in SMARCA4-deficient tumors, although the efficacy of monotherapy remains limited and heterogeneous (15). Consequently, combination treatment strategies have attracted increasing attention. A retrospective study reported superior efficacy of combined chemotherapy and immunotherapy compared with chemotherapy alone in advanced SMARCA4-dADC, with acceptable safety (14). In addition, emerging evidence suggests that ICIs combined with anti-angiogenic agents may exert synergistic effects. A case report showed that first-line PD-1 inhibitor plus anti-angiogenic therapy achieved tumor control and survival benefit in chemointolerant patients with SMARCA4-deficient NSCLC (6). By contrast, surgery alone for early or locally advanced SMARCA4-dADC has shown limited benefit, and postoperative conventional therapies are frequently associated with treatment resistance. Thus, the optimal therapeutic strategy for SMARCA4-dADC remains to be defined (16). Notably, novel approaches targeting synthetic lethal interactions, such as SMARCA2 inhibition, have demonstrated potent antitumor activity in SMARCA4-deficient models with relatively low toxicity, representing a promising therapeutic direction (17).

Explanations of findings

The favorable response may be attributed to several biological mechanisms. Although SMARCA4 deficiency is associated with an immunosuppressive tumor microenvironment, chemotherapy can induce immunogenic cell death, enhance antigen release, and improve immune priming, thereby sensitizing tumors to immune checkpoint blockade. Moreover, SMARCA4 loss leads to chromatin instability and impaired DNA repair, potentially increasing tumor immunogenicity and susceptibility to combined cytotoxic and immunotherapeutic approaches (18,19). These mechanisms may collectively explain the marked tumor regression and achievement of pCR in this patient.

Implications and actions needed

This case suggests that neoadjuvant chemoimmunotherapy may be a viable treatment option for selected patients with locally advanced SMARCA4-dADC, a subtype lacking established standard therapy. Routine assessment of SMARCA4 status may aid treatment stratification. Prospective studies are needed to confirm the safety and efficacy of this approach and to explore biomarker-driven combination strategies, including emerging SMARCA2-targeted therapies.

Conclusions

To our knowledge, this is the first report of tumor downstaging and pCR following neoadjuvant chemoimmunotherapy and surgery in locally advanced SMARCA4-dADC. These findings warrant validation in larger prospective studies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-332/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-332/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-332/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Publication of this case report and accompanying images was waived from patient consent according to the Ethics Committee of Peking University People’s Hospital (Qingdao Hospital) review board (approval No. 2025PHDQB025-01).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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