Dr. Yaping Xu: Differentiating Lung Injury in Radiotherapy-Immunotherapy Combination, Toxicity Warning, and Translational Research Exploration | WCLC 2026

Editor's Note: From September 12 to 15, 2026, the 2026 World Conference on Lung Cancer (WCLC 2026), hosted by the International Association for the Study of Lung Cancer (IASLC), was held in Seoul, South Korea. FOCUS Clinical Scientists specially invited Dr. Yaping Xu from Shanghai Pulmonary Hospital to share her insights on the mechanistic differences between radiation pneumonitis and immune-related pneumonitis, their clinical implications, and translational research directions in radiotherapy combined with immunotherapy.

FOCUS Clinical Scientists: Radiation pneumonitis and immune-related pneumonitis are highly similar in imaging and symptoms, making clinical differentiation difficult. From the perspective of macrophage-mediated pathophysiological mechanisms, what is the essential difference between these two types of lung injury? What implications does this mechanistic difference have for clinical differentiation, treatment strategy selection, and full-course prognosis management?

Dr. Yaping Xu: Radiation pneumonitis and immune-related pneumonitis are highly similar in imaging and symptoms, but there are essential differences in the macrophage-mediated pathophysiological mechanisms. In radiation-induced lung injury, radiation causes DNA damage in alveolar epithelial cells and vascular endothelial cells, releasing damage-associated molecular patterns (DAMPs), which early on activate M1 macrophages and initiate acute inflammation; persistent injury drives the transformation of M1 macrophages into M2 macrophages, and large numbers of M2 macrophages secrete profibrotic factors such as transforming growth factor-β (TGF-β), ultimately leading to pulmonary fibrosis. In contrast, immune-related pneumonitis is driven by persistently overactivated T cells that continuously stimulate macrophages, maintaining an M1 proinflammatory phenotype, with relatively weak activation of the M2 profibrotic pathway. This mechanistic difference brings three important clinical implications.

First, in terms of diagnosis, one cannot rely solely on chest CT and symptoms such as cough and shortness of breath; treatment timing and imaging characteristics must also be considered. Radiation-induced lung injury typically presents as early acute inflammation, with activation of profibrotic pathways after the acute phase, and most patients slowly progress to pulmonary fibrosis, with lesions mostly consistent with the radiation field. Immune-related pneumonitis, on the other hand, manifests more as active autoimmune inflammation; with timely intervention, lung injury is generally reversible, with less frequent pulmonary fibrosis, and lesions are widely distributed, not limited to the radiation field.

Second, in terms of treatment strategy selection, for radiation-induced lung injury, in addition to controlling acute inflammation, vigilance for subsequent fibrotic progression is needed, and antifibrotic intervention often must be considered; whereas the core of treating immune-related pneumonitis is to suppress abnormally activated autoimmune responses. The two differ in duration of corticosteroid use, tapering rhythm, choice of antifibrotic agents, use of immunomodulators, and subsequent follow-up priorities. At this year's WCLC, a randomized phase II study of thymosin α1 in concurrent chemoradiotherapy combined with immunotherapy for locally advanced non-small cell lung cancer (NSCLC) confirmed that it can reduce the incidence of grade ≥2 pneumonitis and improve treatment completion, suggesting that proactive toxicity-reduction intervention is very important. Our team presented a prospective multicenter single-arm clinical trial at this conference for first-line treatment of extensive-stage small cell lung cancer (SCLC), evaluating the efficacy and safety of thymosin α1 combined with chemo-immunotherapy followed by thoracic radiotherapy, with progression-free survival (PFS) as the primary endpoint and the incidence of grade ≥2 pneumonitis as the secondary endpoint. The study is currently ongoing. We hope these studies will provide prevention and treatment strategies for lung injury associated with radiotherapy-immunotherapy combination in the future.

Third, in terms of prognosis and full-course management, the two types of lung injury differ in their responsiveness to corticosteroids, reversibility, and impact on the long-term benefits of immunotherapy, requiring continuous dynamic assessment during follow-up. By combining macrophage-mediated pathophysiological mechanisms with radiomic features, achieving early differentiation, warning, and precise classification before symptoms and typical imaging appear, and providing proactive prevention and intervention, is of great significance for prolonging survival and improving quality of life in lung cancer patients receiving radiotherapy-immunotherapy combination.

FOCUS Clinical Scientists: From the perspective of translational medicine research, if radiotherapy combined with immunotherapy is to achieve further breakthroughs, which research directions should be focused on? Could you discuss, in light of relevant research advances at this year's WCLC, what noteworthy explorations and preliminary results currently exist in these directions?

Dr. Yaping Xu: Translational research on radiotherapy combined with immunotherapy should not remain at the simple validation of the notion that "radiotherapy can activate antitumor immunity," but should be designed around real clinical pain points.

First, research on radiotherapy modulating the immune microenvironment. On the one hand, radiotherapy can cause tumor cell death, release tumor antigens, activate related pathways, and initiate systemic antitumor immunity; on the other hand, it can also recruit immunosuppressive cells such as macrophages and regulatory T cells (Tregs), building an immunosuppressive microenvironment. The focus of translational research is to find means to amplify the immune-activating effects of radiotherapy while relieving the local immunosuppressive microenvironment, achieving true synergistic enhancement. At this conference, a study from our team found that spatially fractionated radiotherapy can induce systemic antitumor immune effects by inhibiting macrophage expression of Spp1, suggesting that specific targets can be targeted to synergistically enhance the efficacy of radiotherapy combined with immunotherapy.

Second, research on toxicity risk of radiotherapy-immunotherapy combination. Toxicity risk is a major obstacle restricting the implementation of combination regimens. By mining biomarkers from peripheral blood, radiomics, and other sources that can be used for early prediction of lung injury, high-risk populations can be identified before obvious clinical symptoms appear, guiding early intervention. This is the foundation for the safe implementation of radiotherapy-immunotherapy combination. Our team also has related translational research underway. At this year's conference, reports included a prediction model for severe radiation-induced lymphopenia after thoracic radiotherapy, as well as a meta-analysis on the correlation between immune cell radiation dose and survival, providing more quantitative tools for toxicity warning in radiotherapy-immunotherapy combination.

Third, research on radiotherapy techniques and physical dose parameters in relation to immunity. Previously, radiotherapy regimens were mainly formulated based on local tumor control and normal tissue tolerance doses, but different radiotherapy fractionation modes, irradiation ranges, and dose levels produce vastly different immune-activating effects. Translational research needs to answer what combination of radiotherapy techniques and parameters can maximize the induction of antitumor immunity. For example, spatially fractionated radiotherapy combined with immunotherapy has attracted much attention in recent years. Our center reported a single-arm phase II clinical study at this year's conference with an interim analysis including 15 patients with resectable stage IIa to IIIb NSCLC, evaluating the efficacy and safety of neoadjuvant spatially fractionated radiotherapy combined with toripalimab-based immunochemotherapy. The regimen achieved an ORR of 100%, a major pathological response (MPR) rate of 95%, and a pathological complete response (pCR) rate of 55%. A larger-sample phase II study is being submitted, and a phase III study is also underway. Applying new radiotherapy technologies and adjusting physical dose parameters is an important means of optimizing radiotherapy combination treatment strategies.

Fourth, clinical translational validation of novel combination targets. Macrophage reprogramming, the TGF-β pathway, stimulator of interferon genes (STING) agonists, and others have shown potential for synergy with radiotherapy in basic research. Rigorous translational research is needed to screen out drugs that can synergize with radiotherapy without increasing normal tissue toxicity. Our team also had a study presented as a poster at this year's WCLC, a prospective single-arm phase II trial, mainly evaluating the efficacy and safety of spatially fractionated radiotherapy combined with ivonescimab and chemotherapy as induction therapy for locally advanced unresectable NSCLC, aiming to explore the feasibility of combining low-toxicity spatially fractionated radiotherapy with a PD-1/VEGF bispecific antibody. The study is currently ongoing.

In summary, all translational explorations should ultimately serve clinical efficacy enhancement and toxicity reduction, benefiting more patients.

Expert Profile

Dr. Yaping Xu

Shanghai Pulmonary Hospital

Specializes in precision radiotherapy for lung tumors and multidisciplinary comprehensive treatment and translational research involving chemotherapy, immunotherapy, targeted therapy, and other modalities.