Controlled Cold Exposure Combined With PD-1/PD-L1 Immunotherapy in Solid Tumors (NIVALIS)

This study does not alter the participant's predetermined standard antitumor treatment pathway. It is non-randomized, does not include a parallel thermoneutral control arm, and uses an open-label design. A total of 24 participants are planned to obtain 20 evaluable participants. For early safety protection, staggered enrollment will be used: the first 2 participants will complete the first combination intervention and the dose-limiting toxicity observation window before further enrollment proceeds, provided no predefined unacceptable toxicity is observed. Efficacy and mechanistic endpoints will be explored primarily through longitudinal within-participant comparisons and descriptive analyses.

Inclusion criteria

• 1. Age 18-75 years, regardless of sex. 2. Histologically or cytologically confirmed malignant solid tumor. 3. Evaluated by the treating physician or multidisciplinary team (MDT) as currently planned to receive standard PD-1/PD-L1 inhibitor monotherapy or a standard combination regimen containing PD-1/PD-L1 inhibitors.

• Applicable settings include neoadjuvant, perioperative, or conversion therapy, as well as unresectable locally advanced, recurrent, or metastatic disease planned for systemic therapy.

• At least one evaluable lesion; for patients assessed by RECIST 1.1, at least one measurable lesion is required. Patients planned for surgery may also be included if adequate preoperative imaging and postoperative pathological assessment are available, even if RECIST measurability is not fully met.

• ECOG performance status 0-1; selected patients with ECOG 2 may be enrolled at the investigator's discretion if considered able to tolerate the study procedures.

• Expected survival ≥3 months. 8. Adequate major organ function, including hematologic, hepatic, renal, and electrolyte parameters acceptable for clinical study participation.

• Cardiopulmonary function at rest adequate to tolerate the study procedures, without obvious abnormalities indicating intolerance to cold exposure.

• Toxicities from prior antitumor therapy must have recovered to ≤ Grade 1, except for alopecia or clinically insignificant abnormalities judged by the investigator; for patients previously treated with PD-1/PD-L1 inhibitors, at least 4 weeks must have elapsed before enrollment, and prior related adverse events must have recovered or stabilized sufficiently for re-exposure.

• No clear contraindication to cold exposure, and deemed able to tolerate cold exposure combined with immunotherapy by the investigator.

• Negative pregnancy test for women of childbearing potential; participants of reproductive potential must agree to use effective contraception during the study and for at least 3 months after the last dose.

• Able to understand the study objectives, procedures, and potential risks, and willing to provide written informed consent.

• For participants planned for neoadjuvant, perioperative, or conversion therapy, the investigator must confirm that study procedures will not delay planned surgery or other critical treatments.

Exclusion criteria

• 1. Participation in another interventional clinical study or receipt of another investigational treatment within 4 weeks before study treatment initiation.

• Uncontrolled active infection, including but not limited to severe bacterial, viral, or fungal infection, or active tuberculosis.

• HIV infection; chronic HBV or HCV infection with uncontrolled viral replication or unacceptable liver function.

• Known severe hypersensitivity to the intended PD-1/PD-L1 inhibitor or its excipients.

• Active autoimmune disease or a requirement for long-term moderate- to high-dose immunosuppressive therapy; physiological replacement-dose steroids may be allowed at the investigator's discretion.

• Prior severe or life-threatening immune-related adverse events during PD-1/PD-L1 inhibitor therapy that have not resolved or are considered high-risk for re-exposure.

• Significant cardiovascular disease, including but not limited to unstable angina, severe arrhythmia, NYHA class III-IV heart failure, LVEF <50%, or myocardial infarction, stroke, or severe thrombotic events within 6 months.

• Severe chronic respiratory disease, especially conditions likely to worsen under cold stimulation, such as severe COPD or severe asthma.

• Clear contraindications to cold exposure, including prior severe cold-related injury, cold urticaria, cryoglobulinemia, active Raynaud's syndrome, or other diseases judged by the investigator to preclude tolerance to a cold environment.

• Uncontrolled symptomatic central nervous system metastases. 11. Severe psychiatric illness, cognitive impairment, substance abuse, or alcohol dependence that would interfere with compliance.

• Pregnancy or breastfeeding. 13. Uncontrolled diabetes, severe malnutrition, marked frailty, or any other condition judged to make the participant unable to tolerate cold exposure or study procedures.

• Any situation in which study participation may significantly delay standard therapy, planned surgery, or other critical treatment timing.