Cancer, a chronic and dangerous disease, poses a major public health burden. Inflammation and insulin resistance promote tumorigenesis. However, the temporal relationship between the two and their relationship with cancer risk must be elucidated.This study aimed to investigate the association between chronic inflammation, insulin resistance, and the propensity for cancer incidence.We explored the temporal relationship between triglyceride index (TyG) and high-sensitivity C-reactive protein (hsCRP) levels using cross-lagged modeling. We used COX proportional risk regression modeling to explore the association between high cumulative triglyceride and glucose index (CumTyG) and high cumulative high-sensitivity C-reactive Protein (CumhsCRP) and cancer risk. We further stratified CumTyG according to tertiles to explore the association of CumhsCRP with cancer risk at different insulin resistance levels and vice versa. We analyzed the association of combined chronic inflammation with insulin resistance, risk of different cancer types, and all-cause mortality. Finally, we performed two sensitivity analyses, excluding patients who developed cancer within the first year of follow-up and those with hsCRP levels > 10 mg/L.The results of the study showed that the standardized correlation coefficient (β1) between hsCRP_2006/2007 and TyG_2010/2011 was 0.02306, which was significantly higher than the correlation (β2) between TyG_2006/2007 and hsCRP_2010/2011, suggesting that inflammation played a more prominent role in future changes in insulin resistance. Chronic inflammation and insulin resistance are positively and synergistically associated with cancer risk, with high chronic inflammation and high insulin levels increasing the risk of carcinogenesis by 71%. Although CumTyG in different CumhsCRP strata and CumhsCRP in different CumTyG strata promoted carcinogenesis, there were differences in the extent of carcinogenesis. High inflammation and insulin resistance, which promote cancer onset, are closely associated with digestive system cancers. The sensitivity analysis was consistent with the primary results and verified their reliability.This study revealed the potential impact of inflammation on future changes in insulin resistance. There is a synergy and interaction between chronic inflammation and insulin resistance, which promotes the risk of cancer.ChiCTR2000029767 ( https://www.chictr.org.cn/showproj.html?proj=48316 ).February 13, 2020.© 2025. The Author(s).