Immune Therapy Plus Chemotherapy Erases Stage IIIB Lung Tumor Before Surgery

A single patient’s journey from an inoperable lung cancer diagnosis to a cancer-free surgical specimen is offering researchers an unusually detailed window into how immunotherapy reshapes the tumor microenvironment. In a case report published in Heliyon, clinicians describe a 50-year-old man with stage IIIB lung squamous cell carcinoma who received three cycles of the anti-PD-L1 antibody sugemalimab combined with platinum-based doublet chemotherapy before undergoing surgery. When pathologists examined the resected lung tissue, they found no surviving cancer cells at all, a result known as a pathological complete response. Forty-eight months after treatment, the patient shows no signs of recurrence. What makes the report notable is not simply the outcome, but the unusually dense biomarker workup that accompanied it, spanning PD-L1 staining, circulating tumor DNA sequencing, macrophage mapping, and measurements of immunoproteasome expression across three separate tissue sites.

The patient’s disease was discovered almost by accident. During a routine health examination in April 2022, chest computed tomography revealed an irregular mass in the apical segment of the right upper lobe, measuring approximately 5.9 by 5.0 centimeters at its largest cross-section. The lesion sat dangerously close to the mediastinal pleura and the right brachiocephalic vein, and imaging suggested metastatic involvement of right hilar and mediastinal lymph nodes. A percutaneous biopsy confirmed squamous cell carcinoma, one of the two major subtypes of non-small cell lung cancer, supported by a characteristic immunohistochemical profile including strong staining for P63 and cytokeratin markers with negative TTF-1 and NapsinA. Under the eighth edition of the UICC/AJCC staging system, the tumor was classified as T3N2M0, placing it firmly in stage IIIB territory, a stage at which a large proportion of patients are considered inoperable at diagnosis.

Beginning in July 2022, the patient received three 21-day cycles of albumin-bound paclitaxel and cisplatin alongside 1200 milligrams of sugemalimab, an IgG4 monoclonal antibody that blocks the interaction between programmed death-ligand 1 and its receptors on T cells. The only reported toxicity during this period was grade I nausea, a remarkably mild profile for such an aggressive preoperative regimen. After two cycles, a follow-up CT scan showed the tumor had shrunk to roughly 4.8 by 3.7 centimeters, but more striking was the change in its internal character. The soft tissue density had decreased so substantially that the lesion now appeared as a cavity surrounded by minimal ground-glass opacity. By the formal RECIST 1.1 criteria, this counted only as stable disease, a reminder that conventional imaging metrics can dramatically understate the biological impact of immunotherapy, which works by triggering immune infiltration and tissue remodeling rather than rapid tumor collapse.

Surgery took place on October 10, 2022, in the form of video-assisted thoracic surgery with right upper lobectomy and systematic lymph node dissection. The pathological examination told a story the CT scans had only hinted at. The lung interstitium showed extensive fibrosis, lymphocytic infiltration, aggregates of multinucleated giant cells, and small focal calcifications, the archaeological traces of a tumor that had been dismantled by the immune system. Microscopy revealed no definite residual cancer anywhere in the specimen. The bronchial margins were clear, the visceral pleura was uninvolved, and none of the dissected lymph nodes contained metastatic disease or even treatment-related fibrosis, yielding a pathological stage of ypT0N0. The patient then completed one additional cycle of immunochemotherapy after surgery, followed by a planned year of sugemalimab maintenance monotherapy, a strategy embedded in the team’s prospective perioperative chemoimmunotherapy trial registered as NCT04941417.

The case sits within a rapidly shifting treatment landscape. For decades, surgery followed by adjuvant chemotherapy was the standard approach for resectable stage II to III non-small cell lung cancer, yet adjuvant chemotherapy improved five-year overall survival by only about five percentage points. The introduction of immune checkpoint inhibitors changed that calculus. The CheckMate 816 trial, the first phase 3 study of neoadjuvant chemoimmunotherapy in stage IB to IIIA disease, demonstrated that adding the anti-PD-1 antibody nivolumab to chemotherapy raised the pathological complete response rate from 2.2 percent to 24.0 percent and extended event-free survival from 20.8 to 31.6 months. More recently, the KEYNOTE-671 trial tested perioperative pembrolizumab in stage IIA to IIIB patients and met both of its dual primary endpoints, with median event-free survival of 47.2 months compared to 18.3 months with placebo, and a clear overall survival advantage. Despite lingering debates over whether patients who achieve a complete pathological response still need postoperative immunotherapy, neoadjuvant chemoimmunotherapy is now firmly embedded in clinical practice.

What distinguishes this report is the effort to understand why this particular patient responded so completely, and the investigators approached that question from several angles simultaneously. Baseline immunohistochemistry using the Dako 22C3 assay showed a tumor proportion score for PD-L1 of just 5 percent, a level generally considered low and, on its own, a poor predictor of benefit from checkpoint blockade. That finding underscores a persistent problem in the field: PD-L1 expression alone fails to capture the complexity of immunotherapy response, particularly in squamous histology, where the immune landscape differs markedly from that of lung adenocarcinoma. Previous work has shown that lung squamous cell carcinoma carries a predominantly immunocompromised signature, including heavy infiltration of M2-polarized macrophages into tumor islets and downregulation of complement cascade genes.

To probe that microenvironment directly, the team employed multiplex immunofluorescence on baseline and post-treatment specimens, using DAPI to label all cell nuclei, pan-cytokeratin to mark cancer cells, CD68 as a pan-macrophage marker, CD86 and IRF5 to identify pro-inflammatory M1 macrophages, and CD163 and CD206 to flag immunosuppressive M2 macrophages. The results painted a picture of an immune landscape tilted toward tumor promotion. In the baseline primary tumor, M1 cells numbered 11 per square millimeter while M2 cells reached 77 per square millimeter. After treatment, the resected tumor bed showed a single M1 cell against 103 M2 cells per square millimeter, yet the resected lymph node told a different story, with the M1-to-M2 density gap narrowing to a difference of 22 per square millimeter compared to 102 in the tumor bed. The authors interpret the lymph node finding as evidence of a pro-anti-tumor environment in the tumor-draining lymph nodes, consistent with the favorable clinical outcome. Preclinical studies support this reading: anti-PD-L1 antibodies have been shown to remodel the macrophage compartment toward a more proinflammatory phenotype through interferon-gamma signaling, and sugemalimab specifically has been reported to upregulate M1 macrophages while suppressing myeloid-derived suppressor cells.

The investigators also examined the immunoproteasome, a specialized form of the proteasome complex whose catalytic subunits PSMB-8, PSMB-9, and PSMB-10 are induced by interferon-gamma and tumor necrosis factor-alpha under inflammatory conditions and are implicated in antigen presentation, tumor invasion, and lymph node metastasis. Using quantitative H-score analysis with QuPath software, they found that expression of all three subunits peaked in the resected lymph node samples. PSMB-8 scored 195 in the primary lesion, 239 in the lymph node, and 191 in the tumor bed; PSMB-9 scored 145, 155, and 126 respectively; and PSMB-10 scored 181, 200, and 197. When binned into low, intermediate, and high categories, PSMB-9 and PSMB-10 expression proved broadly similar across the three sites, with only PSMB-10 appearing meaningfully elevated in the lymph nodes. The authors caution that a single case cannot establish mechanism, but they suggest that PSMB-8 inhibition and its relationship to anti-tumor outcomes in tumor-draining lymph nodes merit systematic exploration.

Perhaps the most clinically translatable finding came from the liquid biopsy. Using next-generation sequencing targeting 425 tumor-related genes on plasma samples collected before treatment and after one cycle of neoadjuvant therapy, the team measured a baseline tumor mutational burden of 4.1 mutations per megabase with six detectable somatic mutations. After a single cycle of chemoimmunotherapy, circulating tumor DNA fell to zero, a complete molecular clearance that preceded both the radiographic response and the pathological one. Circulating tumor DNA has emerged as a promising non-invasive marker of molecular residual disease, capable of signaling recurrence or metastasis before standard imaging can detect it. In this case, the early clearance complemented the imaging assessment as a predictor of treatment response, and the authors argue that ctDNA surveillance could eventually help determine which patients with complete pathological responses can safely forgo or shorten adjuvant therapy, a question that remains unresolved.

The report’s authors, led by Ziyi Xu and Puyuan Xing of the National Cancer Center in Beijing, are careful to frame the findings appropriately. A single patient cannot prove that sugemalimab plus chemotherapy is superior to alternatives, and the biomarker observations, from macrophage polarization to immunoproteasome expression, are hypothesis-generating rather than definitive. Yet the case illustrates a broader convergence in oncology: treatment decisions increasingly informed not just by what a tumor looks like under the microscope, but by the molecular conversation it conducts with the immune system. The patient, a heavy smoker with a 30-pack-year history whose tumor expressed low levels of PD-L1, would have been difficult to flag as a responder using any single conventional marker. It was the combination of pathological response, molecular clearance in the blood, and microenvironmental shifts across three tissue compartments that revealed the depth of the treatment effect. As the investigators note, PD-L1 status, circulating tumor DNA dynamics, and tumor microenvironment characteristics together form a set of hallmark features indicative of clinical outcomes, and larger prospective studies will be needed to determine which of these signals can reliably guide therapy for the many stage IIIB patients whose tumors remain stubbornly inoperable.

Subject of Research: Neoadjuvant anti-PD-L1 immunotherapy combined with chemotherapy for stage IIIB lung squamous cell carcinoma and associated predictive biomarkers

Article Title: Case report of neoadjuvant treatment with sugemalimab combined with platinum-based doublet chemotherapy in stage IIIB lung squamous cell carcinoma and research in potential biomarkers

Article References: Xu, Z., Chen, D., Xie, T., Shao, K., Li, Y., Ying, J., Li, J., & Xing, P. (2026). Case report of neoadjuvant treatment with sugemalimab combined with platinum-based doublet chemotherapy in stage IIIB lung squamous cell carcinoma and research in potential biomarkers. Heliyon, 12(15), Article e45473. https://doi.org/10.1016/j.heliyon.2026.e45473

Image Credits: AI Generated

DOI: 10.1016/j.heliyon.2026.e45473

Keywords: lung squamous cell carcinoma, sugemalimab, neoadjuvant chemoimmunotherapy, pathological complete response, PD-L1, circulating tumor DNA, tumor mutational burden, tumor microenvironment, macrophage polarization, immunoproteasome, non-small cell lung cancer, biomarkers