A 78-year-old man visited the authors’ hospital complaining of chest tightness, cough, sputum, right back pain, and lower limb edema for 2 months; he was later diagnosed with squamous lung cancer of stage IVB (cT4N3M1) with brain metastasis (). He had hypertension for 30 years, diabetes for more than 20 years, coronary heart disease for 2 years, and colon cancer treated by surgery 6 years ago; hypertension and diabetes were well-controlled by medication and no repeated infectious complications have occurred. He was an ex-smoker with 30 packs per year. The tumor cell proportion score (TPS) for PD-L1 staining was 40%. The patient received one cycle of pembrolizumab (200 mg, day 1) and albumin-bound paclitaxel (nab-paclitaxel, 100 mg/m2, days 1 and 8), followed by brain tumor cyberknife radiation (30 Gy/2F). He was hospitalized in the cardiology department after the first cycle of treatment due to breathlessness and lower limb edema and was diagnosed with cardiac insufficiency (grade 2). Electrocardiogram (ECG) and echocardiography were applied; ECG showed sinus rhythm with STT changes similar to before chemoimmunotherapy, and echocardiography suggested enlarged left atrium, left ventricular systolic dysfunction, and no decrease in left ventricular ejection fraction (LVEF 52%). Serum evaluation of the patient during this period showed that the main abnormal factor was NT-ProBNP (3,840 pg/ml and eight times higher) but TNI was just slightly elevated (63.6 ng/L), CK-MB was 2 ng/ml (within the normal range), and LDH was 383 U/L (slightly elevated). The factors decreased quickly and the symptoms were relieved after medical treatment. Considering the intolerability of chemoimmunotherapy of the patient, the potential cardiotoxicity of nab-paclitaxel, and the patient’s situation, intravenous chemotherapy was stopped and changed to anlotinib hydrochloride capsules (12 mg days 1 to 14) in combination with pembrolizumab (200 mg). Forty-four days after the first administration and two therapy cycles of pembrolizumab, grade 4 neutropenia categorized by Common Terminology Criteria for Adverse Events (CTCAE 5.0) was detected (). A complete blood count showed as follows: white blood cell: 500/μl, neutrophils: 0/μl, Hb: 10.7g/dl, and platelets: 19.7 × 104/μl (). The tumor progressed after pembrolizumab treatment per imaging evaluation (). He was hospitalized and treated with continuous recombinant human granulocyte stimulating factor injection (rhG-CSF, 300 mg, bid) for 11 days; however, neutropenia continued to deteriorate, and the timeline for absolute neutrophil count (ANC) with pembrolizumab administration is shown in. After 11 days of continuous rhG-CSF treatment without any improvement, a bone marrow aspiration was performed. Fifty-eight days after the first administration of pembrolizumab and after 11 days of rhG-CSF treatment, a complete blood count showed the following: white blood cell: 460/μl, neutrophils: 0/μl, Hb: 9.9 g/dl, and platelets: 310 × 103/μl (). He also had hypoproteinemia (ALB 24.9 g/ml), liver function was normal [aspartate aminotransferase (AST): 36 U/L, alanine aminotransferase (ALT): 28 U/L, and alkaline phosphatase (ALP): 64 U/L, lactate dehydrogenase (LDH,127 U/L) and procalcitonin (PCT, 0.35) levels were normal. Renal function was slightly abnormal with a creatinine of 149.9 μmol/L and a glomerular filtration rate of 37.9 ml/min. The coagulation system parameters were normal, but after continuous neutropenia status, the sputum culture was positive for Staphylococcus haemolyticus, and the fungal GM test was positive. No evidence suggested infection of HAV, HBV, HCV, HEV, HSV, CMV, EBV, or HPV. The vital signs of the patient were normal with no fever. Physical examination showed lower limb edema. The patient continued using anti-hypertension, anti-diabetes, and anti-hyperlipidemia drugs (levamlodipine, sacubitril valsartan sodium tablets, dapagliflozin, aspirin, clopidogrel, and atorvastatin) alongside the anti-cancer treatment. The bone marrow smear showed that neutrophils are rare, and the biopsy showed that megakaryocytes can be easily seen and that there was no evidence of myelodysplasia. Malignant tumor infiltration to bone marrow was not present (, ). Autoimmune disease detection showed that anti-nuclear antibody (ANA) was positive with a titer of 1:100; other items were normal. After 14 days of G-CSF treatment, the neutrophil of the patient did not have improvement, and myeloid metastasis was excluded through a bone marrow smear; the patient was taken into consideration for ICI-related neutropenia. On the 59th day post-first administration of pembrolizumab, he was treated with intravenous methylprednisolone sodium succinate (MPS; 80 mg/day for 5 days) firstly, which showed a very slow effect. Then, the dose was changed to 200 mg/day for 3 days and 100 mg/day for 3 days, followed by oral prednisolone (PSL; 50 mg/day, cut into half every 3 days). At the same time, rhG-CSF, antibiotic, and antifungal drugs were treated. After 69 days of the first administration of pembrolizumab, the neutrophil count returned to normal (white blood cell: 7,680/μl, neutrophils: 6,940/μl, Hb:10.7 g/dl, and platelets: 13×104/μl). However, he developed severe cerebral infarction, which progressed rapidly, and he was, therefore, referred to the neurology department and died because of neurological problems.