Intra-Lymphatic STI-3031 Using the Sofusa DoseConnect Device for Treatment of In-Transit Melanoma, The Sofusa-2 Study

Inclusion Criteria:

* Age \>= 18 years
* Disease characteristics:

  * Newly diagnosed, recurrent, or previously treated in-transit metastatic melanoma (ITM) confined to a single limb with or without regional lymph node involvement

    * For patients with ITM, one of the following must be true:

      * A visible superficial ITM, non-nodal lesion with longest diameter \>= 1.0 cm in diameter as assessed using a ruler (e.g., skin nodules) NOTE: Documentation by color photography, including a ruler is required OR
      * A malignant regional lymph node with short axis \> 1.0 cm as assessed by computed tomography (CT) scan (CT scan slice thickness recommended to be no greater than 5 mm) OR
      * A non-visible, non-nodal soft tissue mass of the involved extremity with longest diameter \>= 1.0 cm as measured with CT scan, CT component of a positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI)
  * Newly diagnosed, recurrent or previously treated metastatic melanoma of the lymph nodes in lymphatic beds accessible to limb-lymphatic infusion (Example: lower limb lymphatic accessible femoral, inguinal pelvic and/or retroperitoneal lymph node metastases; upper limb: axillary, infraclavicular and/or subclavian lymph node metastases)

    * For patients with lymph node metastases only (non ITM) the following must be true:

      * At least one tumor involved lymph nodes must be \>= 15 mm as assessed by CT, PET or MRI (target lesion by Response Evaluation Criteria in Solid Tumors \[RECIST\])
* Hemoglobin \>= 8.0 g/dL (obtained =\< 15 days prior to registration)
* Absolute neutrophil count (ANC) \>= 1500/mm\^3 (obtained =\< 15 days prior to registration)
* Platelet count \>= 75,000/mm\^3 (obtained =\< 15 days prior to registration)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) (obtained =\< 15 days prior to registration)
* Alanine aminotransferase (ALT) and aspartate transaminase (AST) =\< 3.0 x ULN (obtained =\< 15 days prior to registration)
* Serum creatinine =\< 2.0 × ULN (obtained =\< 15 days prior to registration)
* Calculated creatinine clearance \>= 40 ml/min using the Cockcroft-Gault formula (obtained =\< 15 days prior to registration)
* Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT, aPTT) PT/INR/aPTT =\< 1.5 × ULN or if patient is receiving anticoagulant therapy INR or aPTT is within target range of therapy (Within 15 days prior to registration)
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
* Negative pregnancy test done =\< 7 days prior to registration, for persons of childbearing potential only.
* Persons able to become pregnant or able to father a child must be willing to use an adequate method of contraception while on treatment and for 180 days (6 months) after last treatment dose on this study
* Provide written informed consent
* Rochester only: Willingness to provide mandatory blood specimens for correlative research
* Willingness to provide mandatory tissue specimens for correlative research
* Willing to return to enrolling institution for 3-month follow-up (during the Active Monitoring Phase of the study)

Exclusion Criteria:

* Any of the following because this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown:

  * Pregnant persons
  * Nursing persons
  * Persons of childbearing potential who are unwilling to employ adequate contraception
  * Persons expecting to conceive or father children during the study or within 180 days (6 months) after the last treatment on this study
* Metastatic melanoma beyond in-transit metastases (ITM) and regional lymph nodes (LNs) that cannot be accessed by intralymphatic infusion by DoseConnect (example: visceral or active central nervous system \[CNS\] metastatic disease)
* ITM involving the hands and feet (not accessible to DoseConnect infusion)
* ITM NOT involving a limb (i.e., head, neck, or trunk)
* Prior radiation of ITM that are being evaluated as measurable lesions
* Any of the following prior therapies:

  * Allogeneic hematopoietic stem cell transplantation (HSCT)
  * Solid organ transplantation
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.

  * NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
* Active autoimmune disease requiring systemic treatment \< 2 years prior to registration, documented history of severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents with use of disease modifying agents, corticosteroids, or immunosuppressive drugs

NOTE: Exceptions are allowed for the following conditions:

* Vitiligo
* Resolved childhood asthma/atopy
* Intermittent use of bronchodilators or inhaled steroids
* Daily steroids at dose of =\< 10mg of prednisone (or equivalent)
* Local steroid injections
* Stable hypothyroidism on replacement therapy
* Stable diabetes mellitus on therapy (with or without insulin)
* Sjogren's syndrome
* Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) which is not considered a form of systemic treatment and is allowed

  * Uncontrolled intercurrent illness including, but not limited to:
* Ongoing or active infection requiring systemic therapy
* Interstitial lung disease
* Serious, chronic gastrointestinal conditions associated with diarrhea (e.g., Crohn's disease or others)
* Known history of hepatitis B (i.e., known positive hepatitis B virus \[HBV\] surface antigen \[HBsAg\] reactive)
* Known active hepatitis C (i.e., positive for hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] detected by polymerase chain reaction \[PCR\])
* Known active tuberculosis (TB)
* Symptomatic congestive heart failure
* Unstable angina pectoris
* Unstable cardiac arrhythmia or
* Psychiatric illness/social situations that would limit compliance with study requirements (e.g., known substance abuse)

  * Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  * History of severe hypersensitivity reactions to other monoclonal antibodies or known hypersensitivity to the study intervention or its excipients, indocyanine green (ICG) dye or iodine
  * Prior history of Grade 4 immune related adverse event (irAE) with prior immune checkpoint inhibitor (ICI) therapy or failure to recover (\< Grade 1) from immune-related adverse event(s) from prior ICI therapy
  * Failure to recover from any adverse events related to any of the following therapies received prior to registration:
* Chemotherapy
* Immunotherapy
* Targeted therapies (e.g., dabrafenib)
* Other investigational agents
* Radiation therapy
* Minor surgical or interventional procedure (NOTE: Biopsy of same limb for diagnosis is allowed)
* Major surgical procedure

  * Previously untreated metastatic melanoma (visceral or CNS). NOTE: Patients with previously treated systemic and CNS melanoma who have been free of disease at systemic sites for \>= 12 weeks are eligible for treatment in this study.