Background:
Cancer increasingly co-occurs with major non-communicable diseases (NCDs), creating a compounded burden that complicates clinical management and worsens prognosis.

Objective:
To determine whether an integrated healthy lifestyle pattern reduces the incidence and burden of cancer-related comorbidities and improves survival after cancer diagnosis.

Methods:
We analyzed UK Biobank participants who were free of major NCDs at baseline and had no cancer diagnosis within 180 days of enrollment. The Healthy Lifestyle Index (HLI) was calculated at baseline using six modifiable components (diet, body mass index, waist circumference, physical activity, smoking, and alcohol intake) and categorized into low, intermediate, and high groups. Primary outcomes were incident cancer and cancer-related comorbidity, defined as cancer co-occurring with at least one of four major NCDs (ASCVD, T2D, COPD, CKD); comorbidity burden was further stratified by number and patterns of coexisting NCDs. We characterized cancer–NCD co-occurrence using network analysis by HLI strata and estimated adjusted associations using multivariable Cox proportional hazards models. Overall survival among cancer patients was assessed via Kaplan–Meier analyses stratified by comorbidity burden and HLI.

Results:
Among 400,714 eligible individuals, 37.3% were classified as low HLI (n=149,360), 35.5% as intermediate (n=142,392), and 27.2% as high (n=108,962). Over a median follow-up of 13.8 years, 53,380 participants developed cancer and 16,188 (4.0%) developed cancer-related comorbidity.
Cancer-related comorbidity was strongly patterned by age and sex. Among cancer patients aged <50 years, 85.9% were comorbidity-free, whereas among those aged >62 years, 40.5% had at least one comorbidity; males had higher comorbidity burden than females (35.5% vs 25.1%). Across age–sex strata, low HLI consistently showed the highest incidence of cancer-related comorbidity and higher burden of multiple-NCD comorbidity. Among cancer patients with comorbidity, 75.7% had a single NCD, most commonly ASCVD (43.7%, n=7,071); frequent multi-comorbidity patterns included Cancer+CKD+ASCVD (6.7%, n=1,078) and Cancer+CKD+ASCVD+T2D (1.4%, n=221).
Network analyses demonstrated HLI-stratified differences in cancer–NCD clustering. Low HLI exhibited dense connectivity, especially lung cancer–ASCVD (degree centrality=430), while intermediate HLI showed partial dispersion with a persistent colorectal cancer–ASCVD link (degree centrality=276). High HLI networks were more fragmented.
In Cox models, higher HLI was associated with lower incident cancer (high vs low: HR 0.92, 95% CI 0.90–0.94; intermediate vs low: HR 0.94, 95% CI 0.92–0.96) and substantially lower cancer-related comorbidity (high vs low: HR 0.51, 95% CI 0.49–0.53; Figure 1). Notably, protective associations strengthened with increasing comorbidity count (high vs low HLI: HR 0.62 for one NCD, 0.29 for two, 0.17 for three, and 0.11 for four; Figure 1). Survival analyses showed steeper survival decline with increasing comorbidity burden, and within each comorbidity stratum, cancer patients with high HLI had consistently higher survival probabilities than those with low HLI .

Conclusions:
Adherence to a healthy lifestyle is associated with reduced cancer risk, fewer comorbidities, and improved survival outcomes, underscoring the value of lifestyle interventions in cancer prevention and survivorship care.

Adjusted associations between Healthy Lifestyle Index categories and the incidence of cancer and cancer-related comorbidities. Derived from Cox regression model with the adjustment of age, sex and socioeconomic status; the incidence rate represents the nu