Inflammatory cytokine-associated cisplatin resistance in non-small cell lung cancer and re-sensitization through interleukin-6 receptor blockade

Abstract

Chemoresistance remains a major challenge in non-small cell lung cancer, especially for cisplatin (DDP)-based therapies, which are a mainstay of treatment. In their study, Dai et al investigate how inflammatory cytokines within the tumor microenvironment contribute to DDP resistance. By analyzing tumor samples from 20 non-small cell lung cancer patients and two resistant cell lines (A549/ DDP and SK-MES-1/DDP), the authors show that increased levels of interleukin (IL)-6, IL-8, and tumor necrosis factor-α are linked to resistance. Logistic regression identifies IL-6 and IL-8 as key risk factors. Functional experiments using tocilizumab, an IL-6 receptor antagonist, demonstrate a reduction in DDP half maximum inhibitory concentration, higher apoptosis rates, and decreased migration and invasion in resistant cells. Although the study has certain limitations, such as the analysis of only five inflammatory cytokines in a small, non-stratified patient cohort; it demonstrates that targeting the IL-6 cytokine axis may help overcome DDP resistance. Overall, the study highlights the inflammatory component of the tumor microenvironment as a modifiable driver of chemoresistance and provide a rationale for integrating cytokine blockade into platinum-based chemotherapy regimens to enhance therapeutic response.

Key Words: Non-small cell lung cancer; Cisplatin resistance; Cytokines; Interleukin-6; Tumor microenvironment

Core Tip: Dai et al’s research study explores the association between inflammatory cytokines and cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). Elevated levels of interleukin (IL)-6 and IL-8 were identified as key risk factors contributing to cisplatin resistance in NSCLC. Notably, IL-6 inhibition via the receptor antagonist tocilizumab restored DDP sensitivity and attenuated malignant phenotypes in resistant cell lines, by reducing cell viability, migration, and invasion, while enhancing apoptosis. These findings highlight the tumor microenvironment-cytokine interplay, particularly IL-6 signaling, as a critical determinant and potential therapeutic avenue in overcoming DDP resistance in NSCLC.

INTRODUCTION

Lung cancer continues to be the leading cause of cancer-related mortality worldwide, with an estimated 2.5 million new cases and 1.8-2 million deaths annually[1]. Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases, predominantly includes histological subtypes such as adenocarcinoma and squamous cell carcinoma[2]. Despite advances in molecular diagnostics and targeted therapies, the prognosis for advanced NSCLC remains poor, with 5-year survival rates around 10%-20%[3]. This poor outcome is largely attributable to late-stage diagnosis, tumor heterogeneity, and the development of resistance to standard treatments[4,5].

Cisplatin (DDP), a platinum-based chemotherapeutic agent, remains a first-line therapy for NSCLC, often administered in combination with other drugs or as part of neoadjuvant regimens[6]. Its mechanism of action primarily involves the formation of DNA adducts that interfere with DNA replication and transcription, ultimately inducing apoptosis in cancer cells[7]. However, a substantial proportion of NSCLC patients exhibit intrinsic resistance to DDP, while others acquire resistance during treatment, leading to disease progression and reduced survival[8].

DDP resistance, whether intrinsic or acquired, continues to pose a major obstacle to effective cancer chemotherapy, impacting a substantial proportion of patients. This resistance is driven by a multifaceted interplay of cellular, molecular, and tumor microenvironmental mechanisms[9].

INFLAMMATORY CYTOKINES AS MEDIATORS OF DDP RESISTANCE IN NSCLC

Emerging evidence points to the tumor microenvironment (TME) as a critical modulator of chemoresistance in NSCLC. The TME is a complex, heterogeneous ecosystem comprising cancer cells, stromal fibroblasts, immune infiltrates, endothelial cells, and extracellular matrix components, all of which interact through a network of soluble factors, including cytokines and chemokines[10-12]. Chronic inflammation within the TME not only promotes tumor proliferation, angiogenesis, and metastasis but also fosters resistance to chemotherapy by altering cellular signaling and metabolic pathways. Inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α, have been extensively implicated in these processes[13,14]. For instance, IL-6, secreted by both tumor and stromal cells, activates signal transducer and activator of transcription (STAT) 3 and phosphatidylinositol 3-kinase/protein kinase B pathways, enhancing cell survival, epithelial-to-mesenchymal transition, and resistance to apoptosis[15,16]. Similarly, IL-8 contributes to chemoresistance by promoting angiogenesis, metastatic potential, and drug efflux through adenosine triphosphate-binding cassette transporters[17,18]. Recent reviews have emphasized the dual role of cytokines in lung cancer, where pro-inflammatory mediators like IL-6 and IL-8 can drive oncogenic processes, while anti-inflammatory cytokines may indirectly support tumor tolerance by suppressing immune surveillance[19].

Building on these molecular insights, the clinical implications of cytokine-mediated mechanisms in NSCLC are increasingly evident. Elevated IL-6 and IL-8 levels have been correlated with poor prognosis, reduced progression-free survival, and diminished responsiveness to platinum-based chemotherapy in patients, underscoring their value as both predictive and prognostic biomarkers[20,21]. Targeting these cytokines or their downstream signaling pathways therefore represents a promising therapeutic avenue[22].

In their article, “Overcoming chemoresistance in non-small cell lung cancer: Insights into the influence of inflammatory factors on treatment response”, Dai et al[23] provide an investigation into the role of inflammatory cytokines in DDP resistance[23]. Through a combination of patient tissue analyses and resistant cell line models (A549/DDP and SK-MES-1/DDP), the authors identify elevated IL-6, IL-8, and TNF-α levels in resistant NSCLC samples, with IL-6 and IL-8 emerging as key risk factors for poor DDP response.

A pivotal aspect of this study is its functional validation of IL-6 as a therapeutic target. The authors employed tocilizumab (TCZ), a clinically approved IL-6 receptor antagonist, to restore DDP sensitivity in resistant cell lines. Their findings reveal that TCZ significantly reduces the half-maximal inhibitory concentration of DDP, enhances apoptosis, and inhibits migration and invasion in A549/DDP and SK-MES-1/DDP cells. These results build on previous reports that IL-6 promotes resistance through pathways such as STAT3 and nuclear factor-kappaB (NF-κB), which upregulate anti-apoptotic and DNA repair proteins[24,25].

Beyond the IL-6/IL-8 axis, several other signaling pathways and cytokine networks contribute to the development of chemoresistance in NSCLC. Crosstalk between IL-6/STAT3 and NF-κB signaling promotes a pro-survival transcriptional program that enhances DNA repair, inhibits apoptosis, and supports epithelial-to-mesenchymal transition, thereby facilitating resistance to platinum-based therapies[26]. Similarly, transforming growth factor-β signaling has been implicated in remodeling the tumor microenvironment, inducing immune evasion, and fostering a stem-like phenotype that sustains long-term resistance[27,28].

Moreover, cytokines such as IL-1β and C-C chemokine ligand 2 interact with tumor-associated macrophages and cancer-associated fibroblasts to establish a chronic inflammatory milieu that reinforces tumor progression and drug tolerance[29]. These interconnected pathways suggest that resistance is not solely driven by tumor-intrinsic mechanisms but also by complex intercellular communication within the TME[30]. Understanding these interactions could inform the design of multi-targeted therapeutic strategies that combine cytokine blockade with inhibitors of key downstream pathways, such as Janus kinase/STAT or phosphatidylinositol 3-kinase/protein kinase B, to achieve more durable treatment responses and mitigate acquired resistance in NSCLC patients[31].

The clinical implications of this work are profound, given NSCLC’s high prevalence and poor prognosis, with a 5-year survival rate of approximately 10%-20%[3]. The use of TCZ aligns with ongoing clinical trials, which are evaluating IL-6 inhibition in advanced NSCLC, suggesting a translational path forward[32]. These efforts reflect a broader trend toward targeting the TME to improve therapeutic outcomes in NSCLC, offering preclinical evidence for the therapeutic potential of modulating its inflammatory components.

While the study by Dai et al[23] contributes meaningfully to the field, it also has limitations noted by the authors. Assessing only five cytokines (IL-4, IL-6, IL-8, IL-10, and TNF-α) leaves potentially relevant soluble mediators, such as IL-1β or transforming growth factor-β unexamined, indicating the need for broader cytokine profiling in future research[23]. In addition, the clinical dataset is relatively small and not stratified by key clinicopathological variables (e.g., tumor-node-metastasis stage, histologic subtype, smoking history), which constrains the generalizability of the findings. Nonetheless, the in vitro demonstration of the functional importance of IL-6 signaling represents a meaningful translational step; however, confirmation in vivo using animal models and patient-derived xenografts, will be necessary to substantiate clinical applicability.

At the same time, the broader literature on cytokine-mediated resistance is also limited by heterogeneity in experimental design, small patient cohorts, and the lack of standardized cytokine profiling, which collectively impede reproducibility and clinical translation. Consequently, larger, well-stratified, multicenter studies are needed to validate these mechanisms and to facilitate their conversion into actionable therapeutic targets.

CONCLUSION

Dai et al’s study[23] provides an important contribution to understanding the inflammatory basis of DDP resistance in NSCLC, identifying IL-6 and IL-8 as key mediators and demonstrating that IL-6 inhibition may help reverse resistance phenotypes. By framing chemoresistance as a dynamic and potentially reversible state driven by TME-derived cytokines, the study offers a translational perspective that extends beyond genomic classifications and positions inflammatory signaling as a therapeutic vulnerability. From a clinical standpoint, these findings support the rationale for incorporating cytokine blockade - particularly IL-6R inhibition with agents such as tocilizumab - into platinum-based chemotherapy regimens to enhance treatment response in refractory NSCLC. Moreover, the identification of IL-8 as a co-driver of resistance suggests that combined IL-6/IL-8 targeting could improve patient outcomes, aligning with evidence linking elevated IL-8 to poor prognosis.

Future research should prioritize the validation of these mechanisms in physiologically relevant models, including patient-derived xenografts, and assess their predictive value in clinical cohorts. Parallel investigation of downstream signaling pathways (e.g., STAT3, NF-κB, E2 promoter binding factor, excision repair cross-complementation group 1) may reveal complementary therapeutic targets. Collectively, this work underscores the clinical potential of modulating the TME’s inflammatory components to overcome chemoresistance and improve therapeutic efficacy in NSCLC.