Gastrointestinal (GI) cancers, encompassing malignancies of the esophagus, stomach, pancreas, liver, colorectum, and other digestive organs, remain a significant global health burden. The estimated global incidence of digestive system cancers reached approximately 4.9 million cases, constituting 24.6 % of all new cancer cases worldwide [1]. In the U.S, there is an estimated 362,200 new cases of digestive system cancer in 2025, representing the leading cancer-related deaths with 28.2 % of all new cancer cases [2]. Colorectal cancer (CRC) had the highest incidence among GI cancers, with an estimated 1.9 million new cases worldwide and 154,270 new cases in the US [3]. Pancreatic ductal adenocarcinoma (PDAC), known for its aggressive biology and detection at late stage, was estimated to cause 67,440 new cases and 51,980 deaths, ranking as the third leading cause of cancer mortality [2]. These malignancies collectively accounted for a substantial proportion of cancer-related mortality, with CRC alone responsible for 1044,072 deaths in 2021 worldwide [4]. Despite advancements in screening and early detection in several types of cancer, most GI cancers are diagnosed at advanced stages. The five-year relative survival rate for PDAC remains 13 %, and for liver cancer is 22 %, reflecting limited therapeutic efficacy in most cases [2]. In contrast, localized CRC can have five-year survival rates exceeding 90 %, but only 32 % of cases are diagnosed at this early stage [2], [5].

Treatment modalities for GI cancers involve multimodality approaches. They include surgery, cytotoxic chemotherapy, radiation therapy, and immunotherapeutic targeted therapy either alone or combined with other systemic therapy options. Cytotoxic agents such as fluoropyrimidines, platinum compounds, and irinotecan remain foundational in GI oncology, often used in conjunction with targeted monoclonal antibodies against VEGF (e.g., bevacizumab) or EGFR (e.g., cetuximab) in select CRC subtypes [5]. In recent years, immune checkpoint inhibitors (ICIs), particularly those targeting PD-1/PD-L1, CTLA-4 and LAG3, have demonstrated meaningful activity in select GI tumors-especially microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) CRCs [6]. Also, ICIs alone or combined with cytotoxic chemotherapy have emerged as novel therapy in first line advanced/metastatic hepatocellular carcinoma (HCC) and biliary tract carcinoma (BTC), respectively [7]. In advanced gastric and gastroesophageal junction (GEJ) cancers, ICI combination with chemotherapy is more effective as first line therapy compared to chemotherapy alone [8], [9]. However, the broader utility of ICIs in GI cancers remains limited due to low immunogenicity, poor T cell infiltration and immunosuppressive tumor microenvironment (TME) [10].

Given these limitations, there is increasing interest in cytokine-based immunotherapy as an alternative or adjunct to checkpoint blockade or cytotoxic chemotherapy [11], [12]. It provides a promising strategy to remodel the TME, enhance effector T-cell infiltration, and sensitize “cold” tumors to ICIs or cytotoxic agents [12]. Cytokines are soluble proteins that regulate immune responses through complex signaling cascades, playing dual roles in both promoting and restraining tumor growth depending on the context [13] (Fig. 1). In GI cancers, chronic inflammation, often mediated by cytokines such as IL-6, IL-10, TNF-α, and TGF-β, contributes to immune evasion and tumor progression [14]. Within the complexity of multimodal TME, cytokines and chemokines interplay an essential role in modulating the inflammatory process, promoting or suppressing tumor growth and regional and distant metastasis [14]. As our understanding of cytokine signaling deepens, these molecules are increasingly recognized not only as biomarkers of disease prognosis and predictors of treatment response, but also as direct therapeutic targets which may offer novel avenues to overcome resistance, personalize treatment, and ultimately improve outcomes in GI cancers (Fig. 2). Rational combination strategies of anti-tumorigenic cytokines (e.g. IL-2, IL-12, IL-15, and IL-21) and dual inhibition of pro-tumorigenic cytokines (e.g. IL-1β, IL-6, VEGF and TGF-β) along with PD-L1 or CTLA-4 have shown effective anti-tumor synergy in both preclinical and clinical models [15], [16]. However, the full realization of these approaches depends on advances in cytokine bioengineering and delivery technologies. Innovations in delivery mechanisms including targeted fusion constructs, PEGylated cytokine agonists, and oncolytic or viral vector–based delivery are investigated to overcome systemic toxicity and achieve a sustained localized immune activation. This review highlights the select list of most investigated cytokines in GI cancers, potential therapeutic roles and challenges in the clinical setting.

IL-2 is a crucial cytokine predominantly produced by activated CD4⁺ T cells [13]. It plays a central role in the proliferation and differentiation of T cells, particularly in the expansion of cytotoxic T lymphocytes (CTLs) and the maintenance of regulatory T cells (Tregs). At the molecular level, IL-2 engagement activates the JAK1/3–STAT5 and PI3K–Akt–mTOR pathways, promoting the transcription of genes involved in T-cell survival, granzyme and perforin synthesis, and cytokine production [13]. These downstream effects enhance the cytotoxic functions of natural killer (NK) cells, contributing to the anti-tumorigenic role of IL-2 [13]. However, IL-2 preferential binding to high-affinity IL-2 receptors on Tregs can amplify immunosuppressive signaling within the TME, facilitating immune evasion and context-dependent pro-tumorigenic effects [17]. This dualistic role explains the limited benefit of unmodified IL-2 in CRC and PDAC where a dense stroma and Treg-dominated milieu restrict effector cell trafficking. Clinically, high-dose IL-2 therapy received FDA approval in 1992 for metastatic renal cell carcinoma (RCC) and in 1998 for metastatic melanoma. However, its application has been limited due to severe toxicities, including vascular leak syndrome. To mitigate these adverse effects, research has focused on developing IL-2 variants and delivery methods designed to selectively activate intermediate-affinity IL-2Rβγ complexes expressed on CD8⁺ T and NK cells, while sparing Tregs and vascular endothelium.

Early-phase pan-tumor trials such as ARTISTRY-1 (NCT02799095) investigated nemvaleukin, IL-2 pathway agonist, enrolled 243 patients across various tumor types including GEJ cancer and CRC. The overall objective response rate (ORR) with nemvaleukin monotherapy was 10 % (7/68) and with nemvaleukin + pembrolizumab was 13 % (19/144); durable responses were observed across several tumor types. Nemvaleukin was generally well tolerated and safety was favorable compared to high-dose IL-2. However, the primary publication did not break down ORR specifically by GI tumor subtype, limiting direct efficacy interpretation for specific GI tumor types [18]. Tumor-targeted IL-2 immunocytokine, Simlukafusp alfa-RO687428 trial, has enrolled colorectal and pancreatic cohorts and showed promising immune pharmacodynamics with overall ORR of 5.1 % and disease control rate (DCR) of 27.1 % (NCT02627274) [17].

An ongoing trial ABILITY-1 of MDNA11, a long acting β recombinant IL-2, is in phase I/II as monotherapy and combined with pembrolizumab in advanced solid tumors including PDAC and CRC (NCT05086692). Preliminary key findings for the on-going study showed ORR of 31 % when MDNA11 was used in combination with pembrolizumab and ORR of 40 % as a monotherapy agent in ICI-resistant patients [19]. SAR444245 (THOR-707) is being assessed in the NCT05104567 with disease-specific sub-studies in esophageal squamous cell carcinoma (SCC), gastric/GEJ adenocarcinoma, HCC, and CRC, largely in combination with pembrolizumab or cetuximab. To localize cytokine activity and mitigate systemic toxicity, ongoing trials are also delivering IL-2 directly to tumors. The vvDD-hIL2 program (NCT07001592) uses a tumor-selective oncolytic vaccinia virus to express IL-2 intratumorally and is recruiting patients with multiple GI cancers. A bacterial vector approach, Saltikva, an attenuated Salmonella typhimurium expressing human IL-2, remains active in a Phase II trial (NCT04589234) combined with FOLFIRINOX (5-Fluorouracil, Leucovorin, Irinotecan hydrochloride, and Oxaliplatin) or gemcitabine/nab-paclitaxel in unresectable metastatic PDAC to investigate overall survival (OS) and time to disease progression. (Table 1)