Clinical bottom line
Inhaled anti-PD-1/PD-L1 therapies represent an emerging approach in lung cancer treatment aimed at enhancing local immune checkpoint blockade while potentially reducing systemic immune-related adverse events such as pneumonitis. Current evidence suggests that immune checkpoint inhibitor-related pneumonitis (CIP) remains a significant complication in systemic PD-1/PD-L1 blockade, with variable incidence and severity. Early biomarker changes, including serum KL-6, may help predict pneumonitis development. However, inhaled formulations are still investigational, and their safety, efficacy, and impact on pneumonitis risk require rigorous clinical validation before routine clinical adoption.
What the evidence shows
Systemic anti-PD-1/PD-L1 therapies have revolutionized non-small cell lung cancer (NSCLC) management but are complicated by immune-related pneumonitis, which can be life-threatening. A pooled analysis by Hong et al. (2017) reported treatment-related pneumonitis incidence ranging from 3% to 5% across cancer types, with higher risk in lung cancer patients. Yakymenko et al. (2023) retrospectively characterized CIP in NSCLC patients, highlighting variable onset timing and clinical presentations, underscoring the need for vigilant monitoring.
Lee Sung Yong et al. (2025) identified serial increases in serum KL-6, a mucin-like glycoprotein, as a potential early biomarker for PD-1/PD-L1 inhibitor-related pneumonitis in NSCLC, suggesting a role for noninvasive monitoring to anticipate and manage CIP. Yin Jianqiong et al. (2022) reviewed the immunopathogenesis of CIP, implicating dysregulated T-cell responses and inflammatory cytokines, which may be modulated differently by local versus systemic delivery routes.
Sun Haishuang et al. (2025) reported a novel case of pneumonitis triggered by a bispecific antibody targeting PD-L1 and CTLA-4, illustrating the complexity of immune-related lung toxicity with evolving immunotherapies. These findings collectively highlight the delicate balance between antitumor immunity and pulmonary immune tolerance.
While systemic PD-1/PD-L1 inhibitors are well studied, inhaled formulations are in early development stages, hypothesized to concentrate drug effect within the lung microenvironment, potentially reducing systemic exposure and immune-related adverse events. However, robust clinical data on inhaled anti-PD-1/PD-L1 therapies remain lacking.
Caveats and uncertainty
The evidence base for inhaled anti-PD-1/PD-L1 therapies is currently limited and largely theoretical or preclinical. There are no large-scale clinical trials published to date evaluating their efficacy or safety compared to systemic administration. The incidence and mechanisms of pneumonitis may differ with inhaled delivery, but this remains unproven.
Biomarkers such as KL-6 show promise but require prospective validation in diverse patient populations and treatment contexts. The heterogeneity of CIP presentations and overlap with infection or tumor progression complicate diagnosis and management.
Case reports of pneumonitis with novel immune checkpoint combinations (Sun et al., 2025) underscore the unpredictable nature of immune toxicities, cautioning against extrapolating safety profiles across different agents or delivery methods.
Finally, the optimal patient selection, dosing, and monitoring protocols for inhaled checkpoint inhibitors are undefined, necessitating careful clinical trial design and post-marketing surveillance.
How this may change practice
If inhaled anti-PD-1/PD-L1 therapies prove effective and safer in clinical trials, they could transform lung cancer immunotherapy by minimizing systemic immune-related adverse events, improving tolerability, and enabling combination strategies with other local therapies.
Clinicians should remain alert to the evolving landscape of checkpoint inhibitor delivery methods and continue to monitor for pneumonitis in patients receiving any PD-1/PD-L1 blockade. Incorporating biomarkers like KL-6 into routine surveillance may facilitate earlier detection of pneumonitis and timely intervention.
Until inhaled formulations are validated, systemic PD-1/PD-L1 inhibitors remain standard of care, with established guidelines for pneumonitis management. Multidisciplinary collaboration and patient education about immune-related toxicities remain essential.