We recently published a preclinical work providing a compelling re-interpretation of the role of Interleukin-1β (IL-1β) in non-small cell lung cancer (NSCLC), demonstrating that, in the context of chemo-immunotherapy, IL-1β can significantly enhance anti-tumor immune responses. By promoting tumor-cell intrinsic expression of the chemokine CXCL10 (the key T cell chemoattractant molecule), IL-1β drives the recruitment of CD8⁺ T cells, overcoming resistance to standard platinum-based chemotherapy plus anti-PD-1, in “cold tumors” (1). The implication is provocative: rather than inhibiting IL-1β, inducing its activity (or enabling its production) might sensitize “cold tumors” to immunotherapy.

This paradigm sharply contrasts with the prevailing clinical efforts over the past several years, which have focused almost exclusively on blocking IL-1β. The rationale for blockade came from preclinical studies (2–4) and also from epidemiological and early experimental evidence that IL-1β promotes tumorigenesis, notably the findings from the cardiovascular CANTOS trial, where patients receiving Canakinumab (a monoclonal anti-IL-1β antibody) had reduced incidence and mortality of lung cancer (5). The observation that air pollutants cause the release of IL-1β by lung macrophages, thus resulting in the proliferation of progenitor-like EGFR mutant epithelial cells, strengthened the pro-tumoral action of IL-1β (6).

That led to a wave of trials (the CANOPY program) in NSCLC: first-line, adjuvant, neoadjuvant, and second-line settings. Yet, frustratingly, the vast clinical promise of IL-1β blockade has not materialized so far (7–10).

In the first-line setting, the Phase III trial CANOPY-1 (NCT03631199) combined Canakinumab with pembrolizumab + platinum-based chemotherapy in advanced/metastatic NSCLC. The study did not meet its primary endpoints: median progression-free survival (PFS) was identical between Canakinumab and placebo arms (6.8 months, hazard ratio [HR], 0.85; 95% CI, 0.67 to 1.09; P = 0.102), and overall survival (OS) was not significantly improved (20.8 months vs 20.2 months, HR, 0.87; 95% CI, 0.70 to 1.10; P = 0.123) (7).

In the adjuvant setting, the Phase III trial CANOPY-A (NCT03447769) tested Canakinumab after complete surgical resection and cisplatin-based chemotherapy in stage II/III NSCLC. It failed to demonstrate a statistically relevant benefit in disease-free survival (DFS): median DFS was 35.0 months with Canakinumab vs 29.7 months for placebo (hazard ratio 0.94; 95% CI, 0.78 to 1.14; one-sided P = 0.258) (8).

In earlier-stage, neoadjuvant treatment, the Phase II trial CANOPY-N (NCT03968419) evaluated Canakinumab alone or in combination with pembrolizumab before surgery. The major pathological response (MPR) rate was low and did not significantly improve over pembrolizumab alone (10).

A prior third-line trial, CANOPY-2 (NCT03626545), combining Canakinumab with docetaxel in patients whose disease progressed after chemotherapy and PD-(L)1 therapy, also failed to meet its OS endpoint: median 10.6 months (95% confidence interval [CI], 8.2–12.4) for the canakinumab arm and 11.3 months (95% CI, 8.5–13.8) for the placebo arm (hazard ratio, 1.06 [95% CI, 0.76–1.48]; one-sided P-value = 0.633) (9).

Thus, despite a sound mechanistic rationale and strong epidemiological signals, anti-IL-1β therapy has so far shown no consistent clinical benefit in NSCLC across multiple settings, first-line metastatic, adjuvant, neoadjuvant, or salvage therapy. In a preventive setting, many clinical trials are currently evaluating the effects of canakinumab, including in smoker populations (NCT04789681, NCT05725343, NCT06038526).

The discrepancy between our optimistic preclinical data and discouraging clinical outcomes (the failure of Canakinumab in the CANOPY trials) may be explained by the timing and context matters. Our preclinical data suggest that IL-1β helps activate immune responses when combined with chemotherapy + Immune Checkpoint Inhibitors (ICIs) and turns “cold tumors” into “hot” ones. In contrast, the CANOPY trials attempted to use IL-1β blockade broadly, regardless of immune and stage contexts. IL-1β may still contribute to protumor inflammation (angiogenesis, invasiveness) (6). In KRAS-mutant cases, IL1B-IL1R1 interactions were markedly more prevalent in precursor lesions (100%) than in invasive lesions. These findings highlight the role of IL-1β-IL1-R1 axis and proinflammatory cues in driving oncogenesis of KACs (KRT8 high alveolar intermediate cell) during early LUAD pathogenesis (11). Thus, early inflammatory events drive carcinogenesis, but once a tumor is established, the same cytokine might adopt a different role, more particularly in the right conditions, e.g. under chemo-immunotherapy treatments (Figure 1). Thus, the therapeutic window for IL-1β inhibition may be limited to cancer prevention rather than treatment.

The mechanistic insights from our study prompt to reconsider IL-1β not as a monolithic “bad actor” but as a context-dependent modulator of anti-tumor immunity. Clinically, this suggests a shift in strategy rather than abandonment of IL-1β-targeted therapies. Here are some potentially transformative clinical perspectives:

The failure of Canakinumab in the CANOPY trials was disappointing, but perhaps not surprising in retrospect: those trials were built on the assumption that IL-1β uniformly promotes cancer, and that its inhibition would therefore be beneficial across NSCLC. Our new preclinical data suggest a far more complex reality: IL-1β may not always be the enemy, sometimes, it’s the ally immunotherapy needs.

Translating this insight into the clinic will require a radical shift: from inhibition to precision activation, guided by biomarkers, delivered in a controlled and temporal manner, and integrated into standard-of-care chemo-immunotherapy regimens. Given the burden and poor prognosis of NSCLC, such an effort is more than justified.

In that light, the current state of IL-1β-targeted therapy should not be seen as the end of the story, but rather as the prelude to a new chapter, where controlled modulation of innate immunity may unlock durable responses for patients who currently have few options. From now, the question to block or to induce IL-1β in lung cancer should be addressed and clarified in further clinical trials.