Inclusion Criteria:
1. Adults ≥18 years of age
2. Biopsy-confirmed diagnosis, for primary or recurrent disease (or high clinical suspicion in the opinion of the Investigator)
1. Part 1: Stage 1 to 4 HNSCC
2. Part 2: UPC squamous cell carcinoma of the head and neck with metastatic disease to at least a single cervical node, AND no biopsy proven evidence of the primary cancer's location.
3. Acceptable hematologic status (as standard surgery protocol requires, as determined by the Investigator), kidney function and liver function. Elevations of creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or total bilirubin \>1.5× the upper limit of normal \[ULN\] must be determined to be not clinically significant by the Investigator and approved by the Medical Monitor.
4. Documented negative serum pregnancy test for women of childbearing potential (i.e., premenopausal women with intact reproductive organs and women \<2 years after menopause)
5. Male patients and female patients of child-bearing potential (i.e., premenopausal women with intact reproductive organs and women \<2 years after menopause) must agree to and comply with using medically acceptable contraception including surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, bilateral tubal ligation), intrauterine device, oral contraceptive, contraceptive patch, long acting injectable contraceptive, partner's vasectomy, double-barrier method (condom or diaphragm plus spermicide or condom plus diaphragm), or abstinence during the trial and for 6 months thereafter
6. Agree to abstain from alcohol consumption from 72 hours before Pegsitacianine administration through completion of Study Day 10 (±48 hours) visit in Part 1 and Part 2.
7. Adequate potential for follow up
Exclusion Criteria:
1. Tumors at sites of which the surgeon would assess that in vivo intraoperative imaging would not be feasible.
2. Life expectancy \<12 weeks
3. Karnofsky Performance Status \<70%
4. Hepatic impairment (Child-Pugh score \>5) or significant liver disease including active hepatitis or cirrhosis
5. Lab values or any sign, symptom, or medical condition that in the opinion of the PI would prevent surgical resection
6. Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
7. Pregnant or lactating women
8. Receiving or planned to receive, during the duration of the study, concomitant medication with a high chance of hepatotoxicity, as judged by the PI based on standard protocols within the study center
9. Alcohol consumption within 72 hours before Pegsitacianine administration
10. Received an investigational agent within the shorter of 5 half-lives or 30 days before Pegsitacianine dosing
11. Inability to adhere to the schedule of assessments or any circumstance that would interfere with the validity of assessments performed in the study
12. The PI considers that the patient should not participate in the study
