Most cancer-related deaths are caused not by primary tumor growth but by metastatic dissemination. Lymph node metastases often appear earlier than distant organ involvement and are usually associated with poor prognosis in solid tumors. For a long time, lymph node metastases were considered an intermediate step preceding further spread. However, studies in mice and patients showed that lymph node and distant organ metastases frequently originate from distinct subclones of the primary tumor. No characteristic mutations in key oncogenes were identified to explain these differences. Therefore, it remains unclear whether distinct metastatic routes reflect different survival requirements for tumor cells or more permissive conditions within lymph nodes.
Lymph nodes are key centers of immune regulation. They filter lymph from surrounding tissues and coordinate interactions between immune cells, shaping both local and systemic immune responses. Their early and frequent colonization by tumor cells therefore, appears paradoxical. Previous studies have shown that lymph node metastases can induce immune tolerance and promote distant metastasis by generating tumour-specific regulatory T cells. However, the signals that trigger lymph node metastasis and whether their effects are confined locally or influence distant colonization remain unknown.
Lymph node metastases have also been associated with impaired antitumor immunity and reduced efficacy of immune checkpoint blockade. At the same time, mouse experiments and clinical studies suggest that tumor-draining lymph nodes may be required for effective immunotherapy responses and should not always be removed. This contradiction indicates that the role of lymph nodes after metastatic involvement, as well as the ability of resident T cells to respond to therapy, remain insufficiently understood.
Stanford researchers demonstrated that type I interferon is a key factor directing lymph node metastasis. IFN-I programs tumors to favour lymphatic dissemination while simultaneously limiting their capacity to colonize distant organs, leading to the independent formation of metastases in different tissues. Although lymph node metastases enhance T cell dysfunction, the associated ISG expression increases tumor sensitivity to immune checkpoint blockade. A similar immunotherapy-favorable state can also be induced in distant metastases through IFN-I administration.
Mechanisms Facilitating Lymph Node Metastasis Simultaneously Inhibit Distant Organ Colonization
Distant organ metastases often arise from tumour cell populations that are absent from lymph node metastases, both in mouse models and in patients. This segregation contradicts earlier assumptions that tumour cells must first colonize lymph nodes to acquire traits necessary for further dissemination. These observations are challenging to explain, given that lymph node metastases usually harbour a broader diversity of tumour cells, likely due to continuous lymphatic influx.
Lymph nodes, distant tissues, lymph, and blood represent distinct biological environments, each imposing specific barriers and shaping metastatic phenotypes. Researchers showed that molecular mechanisms that facilitate lymph node metastasis also inhibit distant organ colonization. Specifically, ISG programs support tumour cell survival in lymph nodes by evading immune responses and suppressing immune responses. These include increased MHC I expression, which reduces NK cell cytotoxicity. The same ISG programs directly impair tumor cells’ ability to establish distant metastases.
This finding is consistent with previous studies showing that ISG suppression is a critical step in the development of bone metastasis and in immune evasion. Low ISG expression likely facilitates tumor cell survival in distant tissues through:
- weakened interactions with the immune system;
- reduced recognition by CD8 T cells due to loss of MHC I;
- decreased activation signals for NK cells.
Thus, ISG programs induced by type I interferon play opposing roles – supporting lymph node metastasis while inhibiting dissemination to distant organs.
Preservation of Lymph Nodes During Immune Checkpoint Blockade in the Presence of Lymph Node Metastases
Previous studies in mice and patients suggested that avoiding aggressive lymphadenectomy and preserving tumor-draining lymph nodes may be important for systemic ICB responses, although this approach was considered potentially unfavorable once lymph node metastases were present. The present study showed that while lymph node metastasis enhances markers of lymphocyte dysfunction in the primary tumour, the presence of lymph node metastases can coincide with improved responses to immune checkpoint blockade.
Several factors may explain this:
- During lymph node metastasis, tumor cells acquire ISG programs, including MHC I and PD-L1 expression;
- Close interactions between tumor and immune cells in lymph nodes create conditions favourable for effective lymphocyte responses.
The discrepancy between lymphocyte dysfunction markers and actual therapeutic efficacy may reflect the fact that many such markers indicate both immune activation and functional exhaustion. In addition, the extent of lymph node involvement may be critical – partial preservation of lymph node architecture may allow immune function to persist.
These findings strengthen the rationale for lymph node preservation in patients receiving ICB, not only at early disease stages but also in the presence of lymph node metastases. However, further studies are required to assess ICB responses in patients with lymph node metastases before tumor dissemination.
The Complex Role of Type I Interferons in Antitumor Immunity
For a long time, IFN responses were considered uniformly beneficial for antitumor immunity, but their role is now recognized as more complex. For example, during radiotherapy, IFN-I production can be induced by cellular damage, enhancing antigen presentation and antitumor responses. A similar effect may occur in primary resistance to ICB. In contrast, in acquired resistance, chronic IFN signaling may promote T cell exhaustion. Inhibition of IFN signaling via JAK1 blockade can prevent chronic IFN activation and restore sensitivity to ICB. Additional support comes from observations that patients with autoantibodies against IFN-I often exhibit robust responses to ICB.
Type I Interferon Can Convert Distant, Immunotherapy-Resistant Metastases Into an ICB-Sensitive State
Mouse experiments showed that IFN-I administration increased sensitivity of ICB-resistant primary tumors to immunotherapy. Interferon alone produced only transient effects, but its combination with ICB significantly slowed tumor growth and induced complete responses in one-third of mice, leading to marked survival improvement without observable toxicity.
Analysis of melanoma patients confirmed the association between IFN signaling, lymph node metastasis, and improved survival during ICB therapy. Increased activity of IFN-I response genes during treatment was observed only in responding patients.
In metastatic disease models, lymph node metastases – but not distant lung metastases – were sensitive to ICB. Systemic delivery of long-acting interferon-alpha combined with ICB suppressed primary tumor growth without toxicity and effectively reduced established lung metastases.
Conclusion
Although lymph node metastases and associated primary tumours are more sensitive to immune checkpoint blockade, metastases in other organs often remain resistant, likely because of low ISG activity. Exogenous type I interferon administration increased the sensitivity of such metastases to immunotherapy, converting previously resistant tumors into responsive ones. The main limitation of this approach is toxicity, although the development of modified and synthetic cytokines may overcome this barrier.
Understanding why lymph node and distant organ metastases arise through distinct pathways and how lymph node metastases influence immunotherapy responses has enabled the proposal of a practical strategy to improve treatment efficacy. This strategy involves using IFN-I to confer lymph node–like properties on distant metastases, thereby increasing their sensitivity to immune checkpoint blockade. Insight into this mechanism may help improve treatment outcomes in stage IV metastatic cancer.
Reference
Type I interferon signaling instills divergent metastatic phenotypes and immunotherapy responses
