Immune checkpoint blockade reshapes drug-associated toxicity: a pharmacovigilance atlas of drug-ICI interactions.

BACKGROUND

Immune checkpoint inhibitors (ICIs) are usually treated as direct culprits in immune-related adverse events, but checkpoint blockade may also reset tolerance to other medications. We tested whether ICI exposure reshapes the organization, drug specificity and timing of reported treatment toxicity.

METHODS

We analyzed 13,701,106 deduplicated FDA Adverse Event Reporting System reports from 2016 through 2025. Cancer-restricted reporting associations and cross-organ community detection characterized the ICI-associated toxicity landscape. Adjusted logistic models tested primary-suspect drug x ICI interactions for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, interstitial nephritis, drug-induced liver injury, anaphylaxis and vomiting. Accelerated failure-time models evaluated documented onset according to ICI exposure and checkpoint pathway.

RESULTS

Among 2,365,278 cancer-associated reports, 256,940 contained an ICI. Of 3001 eligible Preferred Terms, 2091 differed between ICI-containing and non-ICI reports at false discovery rate (FDR) <0.05, and four cross-organ toxicity communities emerged. Drug-phenotype associations were reweighted: 71 of 147 eligible pairs had FDR-significant interactions, including 56 amplifications and 15 attenuations. Signals included marked moxifloxacin-SJS/TEN amplification (interaction OR 100.51, 95% CI 38.58 to 261.84), a submultiplicative enfortumab vedotin-SJS/TEN interaction (0.17, 0.13 to 0.23) and omeprazole-interstitial nephritis amplification (10.33, 7.60 to 14.04). Among 64,593 reports with documented onset of 1-365 days, ICI exposure was associated with longer adjusted onset for five of seven phenotypes (time ratios 1.37-1.58); 10 of 19 estimable checkpoint-phenotype coefficients remained FDR significant.

CONCLUSIONS

Checkpoint blockade was associated not simply with additional toxicity, but with a change in treatment context: drug-phenotype associations shifted in both directions, adverse events formed cross-organ structure and documented onset varied by checkpoint pathway. These findings support ICIs as modifiers of drug toxicity and identify specific signals for longitudinal and mechanistic validation.