• Age ≥18 years.

• Advanced solid tumor with measurable disease.

• Subject must have failed or have contraindication to standard therapies.

• For Cohort 1, primary regimen (Regimen 1a): Patients with advanced solid malignancy for which PD1 or PDL1 antibody monotherapy administered on a 3-week schedule is FDA-approved for treatment, who have one or more tumor deposits that are accessible to focused ultrasound treatment, and who are eligible to receive (or to continue to receive) PD1 or PDL1 blockade therapy. Uveal melanoma patients are not eligible for Regimen 1a.

• Note: Participants eligible for this regimen may receive the primary protocol therapy (Regimen 1a) concurrent with PD1/PDL1 antibody therapy if:

⁃ Progressive Disease: subjects with progressive disease following PD1/PDL1 antibody therapy are eligible for this cohort if it is clinically appropriate for them to continue on systemic PD1/PDL1 antibody per the treating clinician even if they did not begin treatment on this trial. Examples may include a patient with a small new lesion but stable disease in other sites, or very slight tumor growth in multiple sites, in a patient without other approved therapy options. Participants who progress following PD1/PDL1 antibody therapy may undergo interval resection of enlarging lesions and still be included in this cohort as long as they have persistent unresectable disease that is accessible to FUSA treatment.

⁃ Response with persistent disease: subjects who have a clinical response (SD or PR) and have residual lesion(s) accessible to FUSA treatment. Participants with PR are only eligible if it is clinically appropriate for them to continue on PD1/PDL1 therapy per the judgement of the treating clinician.

⁃ Stable disease: The majority of clinical responses to PD1/PDL1 blockade occur within 12 weeks but may occur much later. Routine clinical practice commonly includes continuation of PD1 antibody therapy for 1-2 years for patients with stable disease on that therapy. Thus, patients with SD after 12 weeks of PD1/PDL1 therapy per RECIST criteria may be eligible for Regimen 1a if their disease has remained stable on therapy and if their treating provider recommends continuation of PD1/PDL1 therapy even if they were not treated on this trial.

• For Cohort 1, secondary regimen (Regimen 2a): For those patients treated with primary regimen 1a, select participants may be enrolled in a secondary regimen. This would include participants in the following scenarios:

‣ Stable disease.

⁃ Response in lesion treated in regimen 1, but persistent disease or progression in a separate lesion.

⁃ Initial partial response but still persistent disease at the treated lesion.

⁃ Initial response followed by progression at treated lesion or separate site, after discontinuation of PD-1/PD-L1 antibody. If there is a response and then progression at the site treated in Regimen 1 and the residual tumor meets inclusion criteria, this lesion may be re-treated on the secondary regimen.

⁃ Participants with lesions unique from the lesion treated in regimen 1 may enroll in regimen 2 and have additional lesion(s) treated, as long as they meet all inclusion criteria requirements. Up to three lesions may be treated in the second regimen.

• Patients enrolling to Regimen 2a must have a target lesion amenable to intratumoral injection with polyICLC per the treating clinician's discretion. The lesion(s) to be FUSA treated in regimen 2 do not need to include the lesion targeted in regimen 1. The patient must remain eligible for PD1/PDL1 Ab therapy.

• For Cohort 2, primary regimen (Regimen 1b): The following patient subsets would be eligible for the Cohort 2 primary regimen, as long as they have failed (progressed or not tolerated) or are not eligible for all effective available approved therapies known to confer clinical benefit:

‣ Patients with advanced solid malignancy for which PD1 or PDL1 blockade is not FDA-approved.

⁃ Patients with metastatic uveal melanoma

⁃ Patients with advanced solid malignancies for which PD1 or PDL1 blockade is FDA approved but who are not eligible to receive that therapy because of prior failure, toxicity, baseline autoimmune disease, or frailty.

⁃ Patients who previously responded to PD1/PDL1 therapy but then progressed, if there are no other systemic therapies available to them.

• Patients who were previously undergoing PD-1 blockade therapy must not have received a dose within 4 weeks prior to FUSA treatment.

• For Cohort 2, secondary regimen (Regimen 2b): For those patients treated with primary regimen 1a or 1b, select participants may be enrolled in a secondary regimen. This would include participants in the following scenarios:

‣ Stable disease.

⁃ Response in lesion treated in regimen 1, but persistent disease or progression in a separate lesion.

⁃ Initial partial response but still persistent disease at the treated lesion.

⁃ Initial response followed by progression at the treated lesion after discontinuation of PD-1/PD-L1 antibody. If there is a response and then progression at the site treated in Regimen 1 and the residual tumor meets inclusion criteria, this lesion may be re-treated on the secondary regimen. For participants who progress at a site unique from the treated lesion, they may enroll in Regimen 2 and have this new lesion treated, as long as they meet all inclusion criteria requirements.

⁃ Participants with lesions unique from the lesion treated in regimen 1 may enroll in regimen 2 and have additional lesion(s) treated, as long as they meet all inclusion criteria requirements. Up to three lesions may be treated in the second regimen.

• Patients enrolling to Regimen 2b must have a target lesion amenable to intratumoral injection with polyICLC per the treating clinician's discretion. The lesion to be FUSA treated in regimen 2 does not need to be the same lesion targeted in regimen 1. Crossover from primary regimen 1a is allowed if the patient is no longer eligible for continued PD1/PDL1 Ab therapy (e.g. due to autoimmune toxicity), and if there is no other effective systemic therapy option. The length between the FUSA treatments in regimen 1 and regimen 2 should be no less than 6 weeks. Patients who experienced an unanticipated device effect in the primary regimen are not eligible for the secondary regimen.

• One or more dermal, subcutaneous or nodal metastases from an advanced solid tumor. The metastases need to be accessible for FUSA and for biopsy.

• For FUSA:

• The targeted lesion(s) must be visible by ultrasound imaging and meet the following criteria. Brain lesions may not be targeted for treatment.

⁃ Approximately 1 cm (or more) diameter of treatable tumor volume for lesions to be treated with FUSA.

⁃ The target treatment area needs to be contained within a region at least 5 mm from the skin surface and less than or equal to 23 mm from the skin surface.

⁃ The target treatment area must be at a safe distance from all critical structures, including but not limited to ribs or other bony structures, vital organs, named blood vessels or nerves.

⁃ The critical structures, with the exception of the skin, will not be in the pre-focal ultrasound path.

⁃ The anterior-posterior dimension of the treatment area by US should be no less than 9mm.

• For Biopsies:

• Biopsies may be completed with or without image guidance.

• Lesions that have been selected for focused ultrasound or lesions that have been selected for biopsies as untreated controls may have been previously radiated provided:

‣ The tumor site that was previously radiated has progressed.

⁃ A baseline biopsy of the tumor site is obtained following progression and prior to study entry.

⁃ ECOG performance status 0-2.

⁃ Subjects with brain metastases may participate if all of the following are true:

∙ There has been no evident growth of any brain metastasis since the most recent treatment

‣ No brain metastasis is \> 2 cm in diameter at the time of registration.

‣ Neurologic symptoms have returned to baseline,

‣ There is no evidence of new or enlarging brain metastases,

‣ Subjects are not using steroids for at least 7 days prior to registration. Regardless of dose, however, subjects who are on a steroid taper for management of brain metastases are not eligible until 7 days after completion of that steroid taper.

‣ Brain metastases will not be targeted for FUSA treatment.

⁃ Adequate organ function

⁃ Ability and willingness to give informed consent.