This is a non-inferiority, multicenter, randomized phase 3 trial aimed at investigating the impact of individualized primary clinical target volume based on margin expansion on patients' prognosis and complications compared with the consensus primary clinical target volume based on margin expansion and stepwise extension pattern for patients with newly diagnosed non-metastatic nasopharyngeal carcinoma.

The goals of this clinical trial are: a) To confirm whether the local failure-free survival of patients with nasopharyngeal carcinoma whose primary clinical target volume is delineated based on margin expansion is non-inferior to the local failure-free survival of patients whose primary clinical target volume is delineated according to the CSTRO, CACA, CSCO, HNCIG, ESTRO, and ASTRO guidelines and contouring atlas; b) To explore the impact of the individualized primary clinical target volume based on margin expansion on the overall survival, failure-free survival, distant failure-free survival, locoregional failure-free survival, and regional failure-free survival of patients with nasopharyngeal carcinoma; c) To explore the impact of the individualized primary clinical target volume based on margin expansion on radiotherapy-related complications and quality of life; d) To explore the impact of the individualized primary clinical target volume based on margin expansion on the tumor immune microenvironment, along with its underlying biological mechanisms.

For these purposes, we plan to prospectively enroll patients with newly diagnosed non-metastatic nasopharyngeal carcinoma from hospitals in China. The participants will be randomized into the experimental group and the control group. Comprehensive therapy for participants in both groups will be designed based on tumor stage according to the current clinical guidelines for the management of nasopharyngeal carcinoma. During the radiotherapy, the primary clinical target volume will be delineated based on margin expansion for the experimental group, while the primary clinical target volume will be delineated based on margin expansion and local stepwise extension patterns according to the CSTRO, CACA, CSCO, HNCIG, ESTRO, and ASTRO guidelines and contouring atlas for the control group. The prognosis, complications, and quality of life will be compared between the experimental group and the control group.

Inclusion Criteria:

1. Age: 18 Years to 65 Years.

2. Eastern Cooperative Oncology Group performance status ≤1.

3. Patients with newly diagnosed, histologically confirmed nasopharyngeal carcinoma (non-keratinizing subtype).

4. Tumor staged as T1-4N0-3M0 (AJCC 9th).

5. Patients must sign informed consent and be willing and able to comply with the requirements of visits, treatment, laboratory tests and other research requirements stipulated in the research schedule.

6. Women of childbearing potential and male subjects with female partners of childbearing potential must agree to use reliable contraceptive measures from screening to 1 year after treatment.

7. For subjects requiring chemotherapy, the following are additionally required:

   1. normal bone marrow function (white blood cell count > 4 × 10^9/L, hemoglobin > 90 g/L, platelet count > 100 × 10^9/L);
   2. normal liver and kidney function (total bilirubin ≤ 1.5 × upper limit of normal, alanine transaminase and aspartate transaminase ≤ 2.5 × upper limit of normal, alkaline phosphatase ≤ 2.5 × upper limit of normal, creatinine clearance rate ≥ 60 mL/min).

Exclusion Criteria:

1. Active tuberculosis: active tuberculosis within the past 1 year should be excluded regardless of treatment; a history of active tuberculosis > 1 year ago is exclusionary unless prior adequate anti-tuberculosis treatment is documented.

2. Active infection requiring systemic treatment.

3. Previous or concurrent with other malignant tumors, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary cancer.

4. History of radiotherapy, except for non-melanoma skin cancer located outside the target volume of radiotherapy for nasophayngeal carcinoma.

5. Prior or concurrent treatment for local or regional disease other than that specified in the research plan.

6. Pregnant or lactating women (a pregnancy test is required for women of childbearing potential).

7. Contraindications to MRI examination, for example: claustrophobia, allergy to MRI contrast.

8. History of psychiatric disorders, alcoholism or drug abuse, and other situations assessed by the investigators that may compromise the safety or compliance of patients, such as serious disease requiring timely treatment (including mental illness), severe laboratory abnormalities, or family-social risk factors.

9. For participants requiring chemotherapy, the following must also be excluded:

   1. anti-human immunodeficiency virus positive or diagnosed with acquired immune deficiency syndrome;
   2. uncontrolled heart disease (heart failure [NYHA Class ≥ 2], unstable angina, myocardial infarction in past 1 year, supraventricular or ventricular arrhythmia requiring treatment or intervention).

10. For participants requiring immunotherapy, the following must also be excluded:

    1. hepatitis B virus surface antigen positive and Hepatitis B virus DNA > 1000 copies/mL;
    2. anti-hepatitis C virus positive;
    3. active, known or suspected autoimmune disease (including but not limited to uveitis, enteritis, hepatitis, pituitary disease, nephritis, vasculitis, hyperthyroidism, hypothyroidism and asthma requiring bronchodilators, exceptions are type I diabetes mellitus, hypothyroidism not requiring hormone replacement therapy, skin disorders not requiring systemic treatment [such as vitiligo, psoriasis or alopecia]);
    4. previous interstitial lung disease or pneumonia requiring oral or intravenous steroid therapy;
    5. chronic treatment with systemic glucocorticoid (dose equivalent to or over 10 mg prednisone per day, subjects who use inhaled or topical corticosteroids are eligible) or any other form of immunosuppressive therapy;
    6. allergy to macromolecular protein preparations, or any component of PD-1 monoclonal antibody;
    7. receiving live vaccine within 30 days prior to the first dose of PD-1 monoclonal antibody.