This study aims to observe and explore the efficacy and safety of Anlotinib combined with penpulimab in the treatment of radioiodine refractory differentiated thyroid cancer with first-line resistance to angiogenesis inhibitors, and to summarize the treatment experience of population.

Inclusion Criteria:

1. Patients voluntarily joined the study, signed the informed consent;

2. Patients were pathologically confirmed as locally advanced or metastatic differentiated thyroid cancer (DTC), having at least one measurable lesion (Response Evaluation Criteria In Solid Tumors (RECIST) 1.1);

3. Patients≥18 years of age; Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score: 0-2; Expected survival of more than 6 months;

4. Possessing imaging or clinical evidence of disease progression within the first 18 months of enrollment;

5. Progression of at least one anti-vascular drug（no more than 2）；

6. Tg and structural imaging examinations were performed at least twice before enrollment；

7. Meet any of the following while meeting the above 3 items:（1）Lesions were not iodine-avid；（2） The cumulative dose of RAI was ≥ 600 mCi or 22 GBq, with an interval of at least 3 months. （3） Radiographically documented disease progression within 18 months of RAI therapy despite the presence of iodine-131 affinity at the time of RAI therapy;

8. Major organ functions meet the following criteria within 7 days prior to the treatment:

   1. Hemoglobin (Hb) ≥90g/L;
   2. Absolute Neutrophil Count (ANC) ≥1.5×109/L;
   3. Platelet (PLT) ≥80×109/L；
   4. Total bilirubin (TBIL) ≤1.5 times the upper limit of normal (ULN);
   5. Alanine transferase (ALT) and Aspartate transferase (AST) ≤2.5×ULN; If accompanied by liver metastasis, ALT and AST ≤5×ULN； (f)Serum creatinine (Cr) ≤1.5×ULN or Creatinine clearance rate (CCr) ≥60ml/min； (g) The left ventricular ejection fraction was at least 50% of the normal level.

9. Female patients of reproductive age should agree that birth control (such as intrauterine device, birth control pills, or condoms) must be used during the study period and for six months after completion; Having a negative serum pregnancy test within 7 days prior to study enrollment, and must be non-lactating; Male patients should agree to use contraception during the study period and for six months after the end of the study.

Exclusion Criteria:

1. Complicated diseases and history:

   1. Histologic subtypes of thyroid cancer other than the differentiated type (e.g., medullary carcinoma, lymphoma, or sarcoma) could not be enrolled; Patients currently have or had other malignancies within 5years. Cured localized tumors could be enrolled（e.g., Skin basal cell carcinoma）

   2. Subjects with any severe and/or uncontrolled heart disease, including:

      1. According to the criteria of New York Heart Association (NYHA) grade II or above cardiac insufficiency or echocardiography: LVEF (left ventricular ejection fraction) <50%;
      2. Unstable angina
      3. A myocardial infarction had occurred within 1 year before the beginning of the treatment
      4. Clinically significant supraventricular or ventricular arrhythmias require treatment or intervention
      5. QTc ≥450ms (male), QTc ≥470ms (female) (classified by New York heart association, NYHA);

2. Other anti-tumor treatment (including but not limited to chemotherapy, radiotherapy, etc.). were received within 28 days before the beginning of the treatment; TSH suppression therapy was excluded;

3. Patients who have previously used immune checkpoint inhibitors (including but not limited to nivolumab, pembrolizumab, toripalimab, sintilimab, etc.);

5) Patients with hypertension that was not falling to the normal range with antihypertensive medication (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg) were allowed to use antihypertensive treatment to achieve these parameters. Hypertensive crisis or hypertensive encephalopathy.

6) Multiple factors affect the absorption of oral drugs. 7）Patients at risk for gastrointestinal bleeding were not eligible, including the following: (1) patients with active peptic ulcer lesions and fecal occult blood (++); (2) patients with a history of melena and hematemesis within 3 months; 8). Active or uncontrolled severe infection (≥ Common Terminology Criteria for Adverse Events (CTC AE) 2 grade of infection); 9) Patients with concomitant diseases that, in the investigator's judgment, may seriously endanger patients' safety or may interfere with the completion of the study, or are deemed unsuitable for inclusion for other reasons.