• Participant has a histologically or pathologically confirmed diagnosis of Stage IIIC, IIID, or IV unresectable or metastatic melanoma.

• In the investigator's assessment, the participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of \> 6 months.

• Participant is assessed as having at least one resectable lesion (or aggregate lesions) for lifileucel generation.

• Participant must have at least one measurable disease as defined by RECIST 1.1 following tumor resection.

• Participants must have adequate organ function.

• Participants of childbearing potential or those with partners of childbearing potential must be willing to practice an approved method of highly effective birth control.

• Participants who are \> 70 years of age may be allowed to enroll after the investigator discusses with the medical monitor.