Propranolol with Toripalimab and Platinum Chemo before/around surgery in NSCLC

Inclusion Criteria:

1. Sign a written informed consent form before any research-related procedures；
2. Age ≥ 18 years and ≤ 75 years；
3. ECOG PS score 0-1；
4. Have self-awareness, be willing and have the ability to complete the questionnaire (stress score for all patients)；
5. Provide a signed and dated written informed consent form before any mandatory research-specific procedures, sample collection and analysis；
6. Histologically or cytologically confirmed operable stage II-IIIB (N2) non-small cell lung cancer (AJCC 9th edition TNM lung cancer staging）；
7. Requires MDT assessment for the feasibility of radical surgery；
8. No previous anti-tumor treatment, and histological specimens confirmed no EGFR gene sensitive mutations, ALK gene fusion or ROS1 gene fusion；
9. According to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1 version), at least one measurable lesion by imaging. Lesions located within the previous radiotherapy field can be considered measurable if progression is confirmed (within 28 days before the first treatment)；
10. Agree to undergo standard lobectomy/systemic lymph node dissection；
11. Meet the following laboratory indicators (14 days before the first treatment): 1) Blood routine: Absolute neutrophil count ≥ 1.5 × 109/L；Platelet count ≥ 100 × 109/L；Hemoglobin content ≥ 9.0 g/dL (no blood transfusion or no erythropoietin-dependent administration within 7 days). 2) Liver function: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN)；No liver metastasis；Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. For patients with liver metastasis, ALT or AST ≤ 5 × ULN. 3) Kidney function: Serum creatinine (Cr) ≤ 1.5 × ULN or Cr clearance rate ≥ 60 mL/min (Cockcroft-Gault formula), and urine routine test shows urine protein (UPRO) \< 2+ or 24-hour urine protein quantification \< 1 g. 4) Coagulation function: Within 7 days before the study treatment, International Normalized Ratio (INR) ≤ 1.5 × ULN or Prothrombin Time (PT) ≤ 1.5 × ULN；if the subject is receiving anticoagulation treatment, as long as the PT is within the range of the anticoagulant drug, it is acceptable；
12. Cardiac function: American Heart Association (NYHA) classification \< 3；Left ventricular ejection fraction ≥ 50%；Baseline electrocardiogram shows no PR interval prolongation or atrioventricular block；
13. For pregnant women of reproductive age, a urine or serum pregnancy test should be performed 3 days before the first administration of the study drug (day 1 of the 1st cycle) and the result should be negative. If the urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is required. Non-reproductive-aged women are defined as those who have been postmenopausal for at least 1 year, or have undergone surgical sterilization or hysterectomy；If there is a risk of conception, all subjects (regardless of male or female) should use contraceptive measures with an annual failure rate of less than 1% throughout the treatment period until 120 days (or 180 days after the last administration of the study drug) after the last administration of the study drug.

Exclusion Criteria:

1. Concurrent participation in another interventional clinical study or receiving other investigational drugs, unless participating in an observational clinical study.
2. Prior exposure to any anti-PD-1 or anti-PD-L1, PD-L2, CD137, CTLA-4 antibody therapy, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
3. Systemic treatment with Chinese patent medicines with anti-tumor indications or immunomodulatory drugs (including thymosin, interferon, and interleukins; except for local administration to control pleural effusion or ascites) within 2 weeks prior to first dose.
4. Current use of oral or intravenous beta-blockers (e.g., atenolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, sotalol, etc.) that cannot be safely switched to non-beta-blocker alternatives. Current subjects should have a washout period of at least 14 days with adequate transition period.
5. Contraindications to Beta-Blocker Use Hypersensitivity to any component of this product Bronchial asthma or risk of bronchospasm Ketoacidosis and metabolic acidosis Severe or symptomatic bradycardia, atrioventricular block (Grade II or III), sinoatrial block, sick sinus syndrome Cardiogenic shock Right heart dysfunction caused by pulmonary hypertension Congestive heart failure (NYHA Class III or IV) Hypotension (systolic blood pressure \<100 mmHg) Prolonged fasting state Severe peripheral circulatory failure (e.g., gangrene) Symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma Unstable angina or Prinzmetal's angina Concurrent use of rizatriptan benzoate Severe chronic obstructive pulmonary disease (COPD) Uncontrolled Type I or Type II diabetes mellitus (glycated hemoglobin \[HbA1C\] \>8.5 or fasting glucose \>160 mg/dL at screening)
6. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh Class B or more severe cirrhosis.
7. Malignant bowel obstruction (within 3 months prior to informed consent signing) or history of the following conditions: inflammatory bowel disease or extensive intestinal resection (partial colectomy or extensive small bowel resection with concurrent chronic diarrhea), Crohn's disease, or ulcerative colitis.
8. Completion of palliative radiotherapy within 7 days prior to first study drug administration.
9. Clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction.
10. History of psychoactive drug abuse or drug addiction.
11. Known hypersensitivity to active ingredients or excipients of the study drug.
12. Known history of primary immunodeficiency, or ongoing systemic corticosteroid therapy or any other form of immunosuppressive therapy.
13. Use of immunosuppressive drugs within 4 weeks prior to first study treatment, excluding intranasal, inhaled, or other routes of topical corticosteroids, or physiological doses of systemic corticosteroids (i.e., not exceeding 10 mg/day prednisone or equivalent dose of other corticosteroids), or corticosteroids used for prevention of contrast agent allergy.
14. Failure to recover adequately (i.e., to Grade ≤1 or baseline, excluding fatigue or alopecia) from any intervention-induced toxicities and/or complications prior to starting treatment.
15. Receipt of live attenuated vaccines within 4 weeks prior to first study treatment or planned vaccination during the study (inactivated influenza vaccine for seasonal influenza is allowed within 4 weeks prior to first dose; however, live attenuated influenza vaccine is not permitted).

166.Major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to first study treatment, or expectation of requiring major surgery during study treatment; laparoscopic exploratory surgery within 2 weeks prior to first study treatment.

17\. Known symptomatic central nervous system metastases and/or carcinomatous meningitis. Exception may be made for subjects with previously treated brain metastases if the subject's condition is stable (no evidence of radiographic progression for at least 4 weeks prior to first dose of trial treatment, confirmed by repeat imaging showing no new brain metastases or enlargement of existing brain metastases), and no corticosteroid treatment is required for at least 14 days prior to first dose of trial treatment. This exception does not include carcinomatous meningitis, which should be excluded regardless of clinical stability.

18\. Clinically uncontrolled pleural effusion or ascites (subjects who do not require drainage of effusion or in whom effusion does not significantly increase 3 days after stopping drainage may be enrolled).

19\. Bone metastases with risk of paraplegia. 20. Known or suspected autoimmune disease or history of such disease within the past 2 years (subjects with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment within the past 2 years, hypothyroidism requiring only thyroid hormone replacement therapy, and Type 1 diabetes mellitus requiring only insulin replacement therapy may be enrolled).

21.Known active tuberculosis. 22. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

23.Known history of human immunodeficiency virus (HIV) infection (i.e., HIV antibody positive).

24\. Known acute or chronic active hepatitis B virus (HBsAg positive with HBV DNA viral load ≥200 IU/mL or ≥10³ copies/mL) or acute or chronic active hepatitis C virus (HCV antibody positive with HCV RNA positive).

25.Active syphilis infection requiring treatment. 26. Interstitial lung disease requiring corticosteroid therapy. 27. Active or poorly controlled severe infection. 28. Severe cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism); angina requiring treatment; symptomatic peripheral vascular disease; NYHA Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite antihypertensive treatment.

29.History of other primary malignancies within 5 years, except for: Malignancies in complete remission for at least 2 years prior to enrollment with no other treatment required during the study Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence Adequately treated carcinoma in situ with no evidence of disease recurrence.

30.Pregnant or lactating female patients. 31.Other acute or chronic medical conditions, psychiatric conditions, or laboratory abnormalities that may: increase the risk associated with study participation or study drug administration, or interfere with the interpretation of study results, and which, in the judgment of the investigator, render the patient ineligible for participation in this study.