Although considerable progress has been made in diagnostic and therapeutic strategies, cancer continues to represent a major global health burden, characterized by increasing incidence and high mortality [1], [2], [3]. Among these malignancies, gastric cancer stands out as one of the most prevalent and deadly, presenting persistent challenges in terms of early detection and effective treatment [4]. Gastrointestinal (GI) cancers, primarily encompassing malignancies of the esophagus, stomach, and colorectum, rank among the most prevalent cancers worldwide. While arising from distinct anatomical sites, these cancers exhibit overlapping features alongside unique clinical characteristics [5]. Data from GLOBOCAN 2020 indicate that colorectal, gastric, and esophageal cancers collectively accounted for 18.7 % of newly diagnosed cancer cases and 22.6 % of cancer-related deaths, representing the highest incidence and mortality burden among all cancer types. Consequently, GI cancers pose a substantial global public health challenge [5].

Over the past four decades, extensive research has focused on cytokines and their receptors as therapeutic targets and agents in cancer [6], [7]. Preclinical studies have established a strong basis for enhancing the antitumor and immunostimulatory effects of cytokines such as interferons and interleukins (IL-2, IL-7, IL-12, IL-15), while suppressing the proinflammatory and tumor-promoting activities of TNF, IL-1β, and IL-6 [7]. Dysregulated cytokine expression, a hallmark across most human cancers, has driven numerous clinical trials of cytokine-based therapies, demonstrating biological activity but only modest clinical efficacy [7]. Pro-inflammatory cytokines are closely linked to advanced cancer progression, therapeutic resistance, and unfavorable clinical outcomes, including reduced objective response rates, limited disease control, and shorter progression-free and overall survival [6]. Targeting inhibitory pathways in conjunction with cytokine-based therapies may help overcome resistance mechanisms in cancer. Integrating cytokine immunotherapy with immune checkpoint inhibitors holds promise for transforming gastric cancer treatment by reshaping tumor–immune microenvironment interactions and restoring effective antitumor immunity. Ongoing clinical investigations will be crucial in defining the therapeutic potential and optimal application of these strategies in the management of gastric cancer [4]. A wide array of cytokines is produced within the tumor microenvironment (TME), where they play pivotal roles in determining the prognosis of cancer. Depending on the context, cytokines derived from an inflammatory milieu may influence tumor initiation and progression during early stages or promote invasion and metastasis at later phases [8].

Cytokines are fundamental to the survival, proliferation, differentiation, and effector functions of key immune cells, particularly CD8⁺ T cells and NK cells, which drive antitumor immunity [9]. Although their short half-life initially hindered the clinical use of recombinant cytokines, advances in protein engineering have yielded next-generation cytokine formulations with enhanced stability, prolonged bioactivity, and improved therapeutic potential [9]. Cytokine-based therapies face two major and opposing challenges. First, due to their rapid degradation and short half-life in vivo, achieving therapeutic concentrations often necessitates frequent dosing or high systemic exposure. Second, cytokines can trigger widespread immune activation, leading to systemic inflammation and multi-organ toxicity, which limits their clinical applicability [10].

Innovative delivery platforms have been engineered to overcome rapid degradation, enabling targeted cytokine administration and enhancing localized antitumor efficacy while minimizing systemic exposure and associated toxicity in healthy tissues [10]. Lipid- and polymer-based particles, established as drug delivery vehicles, have been used to encapsulate a broad range of cytokines, including IFN-γ, TNF-α, IL-2, IL-12, GM-CSF, IL-15, IL-21, and Leukemia Inhibitory Factor (LIF), for diverse applications such as systemic administration, cancer vaccination, intratumoral injection, and T-cell targeting. Encapsulation protects cytokines from in vivo neutralization, allowing for sustained and targeted paracrine release. This strategy enhances the recruitment and activation of innate immune cells, including macrophages, dendritic cells, neutrophils, and NK cells, while modulating adaptive responses to improve both therapeutic efficacy and safety [11].

In this review, we examine the therapeutic potential of cytokine-based interventions in gastrointestinal cancers and explore how nanotechnology-driven or delivery system–based strategies can achieve targeted cytokine delivery, strengthen antitumor immune responses, and improve immunotherapeutic outcomes for these challenging malignancies. We highlight recent advancements in cytokine therapeutics, nanomedicine, and synthetic biology that reshape cancer immunotherapy approaches. The review summarizes the current challenges in cytokine delivery and nanomedicine translation, evaluates engineering and formulation strategies designed to enhance therapeutic precision, and discusses how emerging fields, such as systems immunology and synthetic biological nanomedicine, can help overcome existing barriers. Finally, we outline future perspectives for developing safe, effective, and personalized cytokine–nanocarrier platforms with potential clinical applicability in gastrointestinal cancers.