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Immune checkpoint inhibitors (ICIs) such as pembrolizumab have substantially improved outcomes in advanced non-small cell lung cancer (NSCLC), including squamous histology, but prolonged exposure may be complicated by immune-related adverse events (irAEs) and opportunistic infections. We report a 58-year-old man with advanced squamous NSCLC who achieved durable tumor control after six cycles of pembrolizumab plus platinum-based chemotherapy, followed by pembrolizumab maintenance monotherapy (18 cycles). During the later course, he developed severe bacterial pneumonia, invasive pulmonary aspergillosis (IPA), and subsequent aplastic anemia (AA)-like bone marrow failure. Despite systemic antifungal therapy and supportive measures, he experienced progressive pancytopenia complicated by massive hemoptysis and ultimately died. This case underscores the dual nature of ICIs: while providing meaningful and sustained antitumor benefit, they may rarely precipitate life-threatening hematologic toxicity and facilitate severe opportunistic infections in a complex immunologic milieu. Close surveillance of blood counts and infectious complications is warranted during long-term ICI therapy; unexplained cytopenias or new/worsening radiologic abnormalities should prompt early bone marrow evaluation and comprehensive microbiologic work-up. Metagenomic next-generation sequencing (mNGS) may offer useful adjunctive evidence in diagnostically challenging infections, particularly when invasive sampling is not feasible, but results should be interpreted in conjunction with clinical and radiologic context within a multidisciplinary framework.