Chronic inflammation and cancer: ASCO 2025 update

Risk of colorectal cancer, a leading cause of cancer-related mortality worldwide, is strongly shaped by chronic inflammation. Western-style diets—characterized by high intake of highly processed foods, high-fat and high-sugar products, and low intake of fiber-rich products such as fruits or vegetables—have been shown to negatively affect microbial metabolism and promote inflammation, thereby increasing colon cancer risk [9].

In this context, a retrospective analysis of 796 patients with colon cancer (Abstract #3618) found that diets high in ultra-processed foods were associated with markedly elevated systemic inflammatory markers (i.e., C‑reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor [TNF]-α) and an increased cancer risk (adjusted odds ratio [aOR]: 2.47, 95% confidence interval [CI]: 2.01–3.03). By contrast, anti-inflammatory diets, rich in omega‑3 fatty acids and polyphenols, were linked to reduced inflammation [10].

Complementing these findings, a prospective analysis nested into a randomized phase 3 trial of adjuvant therapy in patients with stage III colon cancer (CALGB/SWOG 80702 Alliance study, Abstract #LBA3509) showed that individuals with the highest inflammatory diet scores, as measured by the Empirical Dietary Inflammatory Pattern (EDIP), had significantly diminished overall survival (multivariable hazard ratio [HR]: 1.87; 95% CI: 1.26–2.77). Further, patients who combined an anti-inflammatory diet with higher levels of physical activity (≥ 9 MET h/week) showed the most favorable outcomes in this cohort [11].

These results can also be seen in light of the recently published CHALLENGE trial [12], also presented at ASCO 2025 [13], which impressively demonstrated improvement of disease-free survival (DFS; 5‑year DFS HR: 0.72; 95% CI: 0.55–0.94; p = 0.017) as well as overall survival (OS; 8‑year OS HR: 0.63; 95% CI: 0.43–0.94; p = 0.022) in patients with stage III colon cancer undergoing a structured physical exercise program after adjuvant chemotherapy [13].

This adds to the emerging evidence of lifestyle-based primary and secondary prevention strategies and their potential impact on systemic inflammation levels. While easily accessible and implementable, such lifestyle interventions require high compliance and motivation of patients as well as the support of their social environment to maximize effectiveness. Further, the underlying complex mechanisms of dietary and exercise-induced anti-tumorigenic and immune-modulating effects are not fully understood yet.

Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and the systemic inflammation index (SII; calculated as platelet count × NLR) are simple blood-based markers of systemic inflammation, which have been already associated with adverse outcomes in many different settings including solid cancers [14].

Systemic inflammation is an overarching disease mechanism and also plays an important role in the development of cardiovascular diseases [15]. In Abstract #e20026, the role of chronic systemic inflammation in mediating cardiovascular adverse events in older patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy was investigated. Among 1472 patients ≥ 50 years of age, the study found that the proportion of the total effect mediated by inflammation, as measured by NLR, was higher in the treatment group (12.67%, p = 0.008) than in the control group (9.88%, p = 0.008). Therefore, monitoring inflammation in patients with NSCLC undergoing cytotoxic therapy could be informative to reduce treatment-related cardiovascular risk [16].

Interestingly, inflammation does not always correlate with negative outcomes. Abstract #8525 investigated early cytokine dynamics in patients with NSCLC receiving chemo-immunotherapy (platinum, pemetrexed, and pembrolizumab). Inflammatory cytokines such as IL‑6 and monocyte chemoattractant protein (MCP)-1 rose sharply within 3 days post-treatment. Notably, an early increase in MCP‑1 was independently associated with significantly longer PFS, suggesting that acute inflammatory responses may also reflect immune activation and predict therapeutic efficacy in this setting [17].

This selection of abstracts demonstrates how easily accessible inflammatory markers may be of prognostic relevance. However, these indices are quite unspecific and only inadequately describe the complexity of cancer-associated inflammation. Standardized assessment tools that are prospectively validated to define and quantify systemic inflammation processes are urgently needed to improve therapy tailoring as well as to implement anti-inflammatory therapeutic concepts.

Diagnosis and treatment of solid cancers are associated with diminished quality of life (QoL). Cancer and treatment-associated systemic inflammation has been discussed as a mechanism promoting cancer-related fatigue (CRF) or depression [18]. In 1456 patients with pancreatic ductal adenocarcinoma (PDAC) treated at the Memorial Sloan Kettering Cancer Centre (MSKCC), patients with depression had higher inflammatory markers such NLR, MLR, and PLR (Abstract #e24059). Besides unresectable disease and lower BMI, increased NLR (OR: 1.491, 95% CI: 1.061–2.104) was an independent predictor of depression [19].

Another abstract (Abstract #556) investigated a link between CRF and inflammatory markers (so-called inflammatory polygenic risk score [iPRS], a composite measure of CRP, white cell count, platelet count, NLR) in 802 women with non-metastatic breast cancer before and after standard-of-care chemotherapy. Fatigue symptoms increased during the course of treatment, with iPRS significantly associated with a decrease in fatigue symptoms [20].

While the mechanistic link of systemic inflammation to these complex symptoms is only poorly understood, mitigating systemic inflammation could offer a promising target to increase QoL in cancer patients.

Clonal hematopoiesis (CH), an age-associated condition defined by the expansion of hematopoietic stem cells carrying somatic driver mutations, has emerged as a key link between hematopoiesis, inflammation, and cancer. Beyond its established epidemiological association with cardiovascular diseases and hematologic malignancies, CH is now understood to be an imprint of a pro-inflammatory phenotype on peripheral immune cells, thereby acting as a systemic mediator of chronic inflammation [21, 22]. It has been established that mutations in genes such as DNMT3A, TET2, and ASXL1, among others, alter transcriptional programs in myeloid immune cells such as neutrophils or monocytes. This promotes inflammation by activation of several sterile innate immune signaling pathways including the NLRP3–IL-1β or the cGAS–STING–type I-interferon axis sustaining systemic inflammatory signaling and contributing to disease pathogenesis [22‐25].

Recent work has extended this paradigm into solid tumors. In a large multi-cohort study, Pich et al. demonstrated that tumor-infiltrating immune cells frequently harbor CH mutations, revealing that CH-derived clones not only circulate systemically, but also integrate into the TME [26]. The presence of such tumor-infiltrating CH (TI-CH) has been associated with adverse clinical outcomes in patients with NSCLC. It was found that TI-CH significantly increased the risk of recurrence or death (HR: 1.80; 95% CI: 1.23–2.63) and was linked to higher all-cause mortality across several solid tumor entities. Mechanistically, TET2-mutant infiltrating cells displayed transcriptional signatures of exacerbated inflammatory activation and impaired antigen presentation, suggesting a role in promoting tumor progression as well as dampening effective anti-tumor immunity [26].

These findings support a model in which CH actively shapes the inflammatory TME. By fueling chronic cytokine signaling, recruiting myeloid cell populations, and skewing immune responses toward tumor tolerance, TI-CH emerges as a novel, genetically imprinted source of cancer-associated inflammation with major prognostic implications.

In line with this, Abstract #e23318 investigated the prevalence of CHIP in tissue samples from 138,501 patients with solid tumors from the AACR Project GENIE. Even after excluding TP53 mutations, which are common in both hematologic and solid cancers, CHIP-related mutations were identified in approximately 35% of cases. In contrast to the previously published data from MSK-Impact and TRACERx cohorts, the most frequent mutations were found in SETDB1 (5.65%), SETD2 (5.13%), or CREBBP (4.83%), which are mutations with vital roles in AML with granulo-monocytic differentiation. Mutations typically associated with aging-related CH such as DNMT3A, TET2, or ASXL1 were found at a much lower frequency (2.31%, 3.35%, and 3.33%, respectively; [27]). These surprising differences in distribution and prevalence of key somatic drivers could be explained by the methodological approaches in calling TI-CH variants. We speculate that the data presented in this abstract could be biased by mutations derived from tumor cells and were not exclusively filtered for blood-derived CH variants as performed by Pich et al. [26]; however, full methodological details are lacking to date.

Together, these findings underscore that CH is not merely an age-related background phenomenon but a clinically relevant modifier of the tumor microenvironment and thereby a possible risk factor for therapy-associated adverse outcomes [27].