What Happens When Melanoma Spreads to the Lungs?

When melanoma spreads to the lungs, tumor cells that broke away from the original skin cancer establish new growths in lung tissue, typically appearing as round nodules scattered through one or both lungs. The lungs are among the most frequent landing sites for metastatic melanoma, and the consequences range from no noticeable symptoms at all in the early phase to progressive breathing difficulties, cough, and chest pain as the disease advances. What makes lung metastases particularly interesting to researchers is that the lung’s immune environment is unusually active compared with other organ sites, a feature that shapes both how the disease behaves and how well it responds to modern treatments.

How Melanoma Cells Reach the Lungs

Melanoma cells enter the bloodstream from the primary tumor or from an intermediate site like a lymph node. Once circulating, they need to stick somewhere, survive, and grow. The lungs are a first-pass organ for venous blood, which partly explains why they catch so many circulating tumor cells. But the process is more deliberate than simple filtering. Research in animal models shows that a signaling molecule called angiotensin II can ramp up a sticky protein called E-selectin on the inner lining of lung blood vessels, helping melanoma cells grab hold and anchor themselves there. Blocking E-selectin with an antibody suppressed lung metastasis formation in those experiments, confirming that this adhesion step is not just incidental.

1PubMed. Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells

More recent work has uncovered another layer: the age of the tissue surrounding the tumor may steer where melanoma goes. A 2025 study found that fat cells in younger tissue secrete a lipid called phosphatidylcholine, which melanoma cells absorb. This activates a signaling chain that shifts the cancer cells’ energy metabolism toward a mode favoring lung colonization. In other words, the metabolic environment of the host tissue can nudge melanoma toward the lungs rather than, say, the liver or brain.

2Cancer Cell. Age-dependent stromal lipids reshape melanoma metabolism and dictate metastatic destiny

Preparing the Ground Before Arrival

Melanoma does not just show up in the lungs unannounced. Tumor cells send out tiny vesicles called exosomes well ahead of the actual metastasis. These exosomes travel through the bloodstream and modify the lung tissue in advance, creating what researchers call a pre-metastatic niche: an environment already primed to welcome and support incoming cancer cells. The modifications include changes to inflammation, blood vessel formation, immune cell behavior, and the structural scaffold of the tissue.

3PubMed Central. Effects of exosomes on pre-metastatic niche formation in tumors

Interestingly, the body is not entirely passive during this remodeling. Exosomes from non-metastatic melanoma cells actually trigger a protective immune response: they boost the number of patrolling monocytes (a type of white blood cell) in the lungs, which can clear arriving cancer cells. Exosomes from aggressive, metastatic melanoma lines do not trigger this response nearly as strongly, suggesting that highly dangerous melanoma has evolved ways to avoid alerting the immune system while still preparing the soil for colonization.

4Nature Communications. Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche

What Lung Metastases Look and Feel Like

Early lung metastases from melanoma often cause no symptoms at all. They are frequently discovered on routine surveillance CT scans rather than because the patient feels something wrong. On imaging, the classic appearance is multiple small, well-defined round nodules scattered through the lungs. Most are solid, but a subset can appear as hazy, ground-glass opacities rather than dense masses. One imaging study found that ground-glass patterns were more common in patients whose original melanoma arose from a mucosal surface (inside the mouth, nasal passages, or similar locations) rather than from skin.

5PubMed Central. Pulmonary metastases from malignant melanoma showing ground-glass opacity nodules

As the disease progresses or if the nodules grow large enough, symptoms begin to appear. Cough, shortness of breath, and chest pain are the most common complaints. In rarer cases, melanoma spreads to the pleura, the membrane lining the lungs. When this happens, fluid can accumulate between the lung and the chest wall. One case report described a patient whose pleural melanoma produced a stubborn, bloody pleural effusion requiring an indwelling catheter and eventually surgery to manage.

6PubMed Central. Pleural Metastatic Melanoma with Refractory Hemorrhagic Effusion: A Case Report

Pleural involvement remains uncommon enough that clinicians can miss it if they are not thinking about melanoma as a possible cause of recurrent effusions, particularly in patients with a melanoma history from years earlier.

7PubMed Central. Pleural Metastatic Melanoma With Recurrent Malignant Pleural Effusions

The Lung’s Immune Environment and Why It Matters for Treatment

Not all metastatic sites are created equal when it comes to immune activity. A detailed study comparing melanoma metastases across the lungs, liver, brain, lymph nodes, and skin found that lung metastases had the highest density of immune cells called macrophages and T cells. T cells in lung metastases were physically closer to the melanoma cells (a median of about 57 micrometers) than in liver, brain, or skin metastases, where the distance was roughly 80 to 130 micrometers. Lung metastases also had the highest density of T cells within striking distance of tumor cells and the highest overall scores for immune cell infiltration.

8Journal for ImmunoTherapy of Cancer. Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites

This sounds like good news, and in many ways it is: a more immune-active environment may explain why lung metastases tend to respond better to immunotherapy drugs than brain or liver metastases. But the picture is complicated. Many of those macrophages in the lungs express PD-L1, a protein that acts as a “don’t attack me” signal to T cells. The T cells themselves often express exhaustion markers like TIM-3, meaning they are present but functionally worn down. The immune system is trying, but the tumor is pushing back.

8Journal for ImmunoTherapy of Cancer. Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites

Newer research has identified an immune-suppressing protein called VISTA that is highly expressed in lung melanoma metastases. In mouse experiments, knocking out VISTA led to significantly fewer lung metastases and more active inflammatory monocytes and macrophages in the lung tissue. The effect appeared to work through the myeloid immune cells (macrophages and monocytes) rather than T cells, opening a potential new angle for drug development.

9Cancer Research. Abstract 6556: The role of VISTA in the lung tumor microenvironment of metastatic melanoma

Genetic Mutations That Favor the Lungs

The genetic profile of a melanoma influences where it is most likely to spread. A study of cutaneous melanoma patients found that tumors carrying an NRAS mutation were roughly two and a half times more likely to metastasize to the lungs compared with NRAS-wild-type tumors.

10PubMed Central. Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

Beyond just favoring the lungs, NRAS mutations seem associated with more aggressive lung disease. One study of patients who had their lung metastases surgically removed found that those with NRAS-mutant tumors developed lung metastases sooner, had larger lesions on average, and experienced shorter survival after the surgery compared with patients whose tumors carried BRAF mutations.

11PubMed Central. Molecular characterization of a selected cohort of patients affected by pulmonary metastases of malignant melanoma

BRAF mutations, the most common driver mutations in melanoma, are also found frequently in lung metastases, but they don’t show the same preferential tropism for the lungs that NRAS does. BRAF and NRAS mutations are both associated with brain and liver metastases as well.

10PubMed Central. Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

Staging and Prognosis

Melanoma that has spread to the lungs falls under stage IV in the standard staging system. Within stage IV, lung-only metastases are classified as M1b, which historically carries a somewhat better prognosis than spread to the brain (M1d) or liver. A real-world study of stage IV melanoma patients confirmed that M1d disease (which includes brain metastases), elevated blood LDH, spread to more than three sites, and higher neutrophil-to-lymphocyte ratios were all associated with worse survival. Age, sex, and BRAF status did not independently predict outcomes in that analysis.

12PubMed Central. Clinical predictors of survival in real world practice in stage IV melanoma

The practical implication is that having melanoma in the lungs alone, with a normal LDH and no brain involvement, represents a relatively more favorable scenario within the stage IV category. That said, “relatively more favorable” still means metastatic cancer, and the stakes remain high.

Immunotherapy and Targeted Drug Treatments

Immunotherapy has transformed the outlook for metastatic melanoma, including cases with lung involvement. The combination of ipilimumab and nivolumab, two checkpoint inhibitor drugs that release different brakes on the immune system, is among the most effective regimens. In one documented case, a long-term melanoma survivor with disease progression including a two-centimeter lung mass was rechallenged with this combination after prior treatment. Imaging after just one cycle showed the lung mass and peritoneal nodules nearing complete resolution.

13PubMed Central. Efficacy of Ipilimumab and Nivolumab Rechallenge in a Long-Term Melanoma Survivor: A Case Report

The robust immune infiltration in lung metastases described earlier likely contributes to why immunotherapy often works well at this site. The T cells are already there, already near the tumor; immunotherapy can remove the molecular brakes holding them back.

For patients whose tumors carry a BRAF mutation, targeted therapy with BRAF inhibitors (like vemurafenib or dabrafenib), often combined with MEK inhibitors, offers another option. Phase III trials have shown that combining BRAF and MEK inhibitors improves both the initial response rate and the time before the disease progresses compared with either drug alone.

14PubMed Central. Recent advances in the treatment of melanoma with BRAF and MEK inhibitors

When Drug Resistance Develops

A persistent challenge with targeted therapy is that resistance almost always emerges. For BRAF inhibitors, resistance can develop as early as two months or as late as 18 months into treatment. The cancer cells find workarounds, often reactivating the same growth signaling pathway the drug was designed to block. They can also switch to entirely different signaling routes to keep growing.

15Genes & Diseases. Melanoma: Molecular genetics, metastasis, targeted therapies, immunotherapies, and therapeutic resistance

One mechanism involves the surrounding tissue itself. Non-cancerous fibroblasts in the tumor’s neighborhood can push melanoma cells into a more invasive state, causing them to shift away from the BRAF-driven pathway that the drug targets and instead rely on an alternative signaling route. This kind of adaptability, where melanoma cells can rapidly switch their molecular identity, makes sustained drug control difficult and is a major reason why combination strategies and sequential treatment plans are the norm.

16Cancer Research. Abstract 927: Fibroblast-induced switching to the invasive phenotype and PI3K-mTOR signaling protects melanoma cells from BRAF inhibitors

Resistance also affects immunotherapy, though through different routes. Rather than genetic mutations in a single pathway, immune resistance tends to involve broader changes in the tumor microenvironment that suppress the immune response or allow cancer cells to hide from immune surveillance. Researchers have identified both tumor-intrinsic changes (mutations, epigenetic shifts) and tumor-extrinsic changes (altered immune cell populations in the surrounding tissue) as contributing factors.

17PubMed. Mechanisms of resistance and predictive biomarkers of response to targeted therapies and immunotherapies in metastatic melanoma

Surgery for Lung Metastases

Surgery to remove lung metastases, called pulmonary metastasectomy, remains a valuable option for carefully selected patients. A multicenter study reported five-year cancer-specific survival of 71% and ten-year survival of 26% after lung metastasectomy. The patients who did best had a long interval between their original melanoma diagnosis and the appearance of lung metastases (more than 24 months), no prior spread to other organs, and a less aggressive growth pattern in their primary tumor.

18Cancers. Surgical Resection of Pulmonary Metastases from Melanoma in Oligometastatic Patients: Results from a Multicentric Study in the Era of Immunoncology and Targeted Therapy

A systematic review and meta-analysis looking across multiple studies confirmed that patients who underwent curative metastasectomy (at any organ site, including the lung) had a significantly lower risk of death compared with those who did not have surgery. The benefit held regardless of whether patients also received modern systemic therapy. Factors linked to worse outcomes after surgery included elevated LDH, male sex, multiple metastatic sites, and a short disease-free interval.

19PubMed. Outcomes After Curative Metastasectomy for Patients with Malignant Melanoma: A Systematic Review and Meta-analysis

Surgery is not for everyone. Patients with dozens of nodules throughout both lungs, or with active disease at multiple organ sites, are generally not candidates for metastasectomy. The approach works best for oligometastatic disease, where only a few, resectable tumors are present.

Radiation for Limited Lung Disease

Melanoma has long had a reputation as a radiation-resistant cancer, but stereotactic body radiotherapy (SBRT), which delivers highly focused, high-dose radiation to small targets, has challenged that notion. A multicenter retrospective study of SBRT for oligometastatic melanoma found that the lungs were the most commonly treated site, making up about 40% of all treated lesions. Local control rates were impressive: roughly 94% at one year and 90% at both two and three years.

20PubMed Central. Stereotactic body radiotherapy as a viable treatment on extracranial oligometastases in melanoma patients: a retrospective multicentric study

Earlier research suggested that the key to overcoming melanoma’s apparent radiation resistance is dose intensity. When aggressive SBRT regimens are used, the local control rates for melanoma match those seen in other cancer types, suggesting that the high doses essentially ablate the tumor tissue in a way that bypasses the cellular repair mechanisms that make melanoma resistant to conventional lower-dose radiation.

21PubMed Central. Stereotactic body radiation therapy for melanoma and renal cell carcinoma: impact of single fraction equivalent dose on local control

SBRT is often combined with immunotherapy in practice. There is growing evidence, still being formalized in clinical trials, that radiation to one tumor site can enhance the immune response against tumors elsewhere in the body, a phenomenon sometimes called the abscopal effect. For patients with a few lung nodules who are not surgical candidates, SBRT offers a noninvasive alternative with strong local results.

Managing Breathlessness and Daily Life

Even when systemic treatment is working, lung metastases can cause symptoms that affect quality of life. Breathlessness is the most common and can be driven by the tumors themselves, fluid around the lungs, anxiety, or pain limiting full chest expansion. A multimodal approach works better than any single intervention. One documented case illustrates the range of strategies available:

  • Airflow across the face: A simple fan directed at the face provided the most immediate relief for one patient, likely by stimulating facial nerve receptors that reduce the sensation of air hunger.
  • Opioids: Low-dose controlled-release oxycodone helped manage both chest wall pain and breathlessness. Opioids at low doses can reduce the brain’s perception of breathing difficulty without dangerously suppressing respiration.
  • Anxiety management: Lorazepam and duloxetine addressed the anxiety component, which often amplifies breathlessness out of proportion to the actual lung compromise.
  • Breathing techniques: Pursed-lip breathing and relaxation exercises helped during acute episodes.
  • Activity modification: Gardening in the cooler morning hours and using raised containers to avoid bending reduced exertion-related breathlessness.

Oxygen therapy, often assumed to be the go-to solution, did not improve this patient’s symptoms subjectively, a finding consistent with broader evidence that supplemental oxygen helps most when blood oxygen levels are actually low, not just when a person feels short of breath.

22PubMed Central. Breathlessness with pulmonary metastases: a multimodal approach

Experimental Approaches on the Horizon

Beyond the established pillars of immunotherapy, targeted drugs, surgery, and radiation, researchers are testing combination strategies that try to make the lung microenvironment more hospitable to the immune system. One experimental approach in animal models combined plant-derived compounds with an anti-PD-1 immunotherapy drug. The combination achieved roughly a 70% suppression rate of lung metastases and extended survival in mice, apparently by normalizing the blood vessels within the tumor and restoring the function of T cells that had become exhausted.

23Journal of Nanobiotechnology. Tanshinone IIA&Icaritin -MPs regulated vascular normalization and restored tumor-infiltrating T lymphocyte function to boost anti-PD-1 therapy in melanoma lung metastasis

The rationale behind this and similar strategies is that tumors grow chaotic, leaky blood vessels that create a low-oxygen environment hostile to immune cells. Fixing the plumbing, so to speak, lets immune cells reach the tumor and function properly. Whether this particular approach translates from mice to humans remains to be seen, but the concept of vascular normalization as a partner for immunotherapy is being pursued across multiple cancer types and represents one of the more promising directions for patients whose lung metastases stop responding to current treatments.