Cancer, a formidable adversary to human health, has long been the focus of intense research efforts aimed at discovering innovative therapeutic strategies. Among these approaches is the systemic administration of recombinant cytokines [1], [2]. Cytokines play a crucial role in modulating the immune system, exerting autocrine and paracrine effects on immune cells, stromal components, and cancer cells within the complex tumor microenvironment [3]. However, clinical application of systemic immunocytokine-based therapies has encountered several challenges. The relatively short half-lives of these cytokines necessitate frequent administration, which can lead to severe dose-limiting toxicities [4], [5], [6]. These limitations have driven researchers to seek alternative approaches that maximize the therapeutic potential of cytokines while minimizing adverse effects [7], [8].

One promising approach involves local administration, which aims to increase cytokine (interleukins) concentrations within the tumor microenvironment. This strategy seeks to trigger a potent antitumor immune response on-site while reducing systemic exposure and its associated risks [1], [9]. Consequently, local combinatorial cytokine therapy has been explored in murine models, often involving viral and non-viral gene therapy vectors. Although this method has shown promise, it carries risks, such as unwanted genomic alterations, immune responses against the delivery vectors, and activation of innate immune system receptors due to vector backbones [10]. In a paradigm shift, messenger RNA (mRNA) has emerged as an ideal therapeutic vehicle to overcome these challenges [11]. mRNA-based therapies offer a unique advantage, enabling transient and localized translation of cytokines. Additionally, mRNA can be delivered with or without specialized formulations, providing flexibility in terms of administration, and can be precisely tailored to enhance translation and activity on innate and adaptive immune receptors [12], [13].

Interleukin-11 receptor alpha (IL11RA) has emerged as a secretory and membrane-bound protein in the context of cancer [14], [15]. IL11RA is a cell surface receptor that belongs to the interleukin-6 (IL-6) family of cytokines. While initially recognized for its role in various physiological processes such as inflammation, tissue repair, and hematopoiesis, recent studies have demonstrated its intricate involvement in cancer biology [16]. Studies have shown that IL11RA and its associated signaling pathways can profoundly influence the tumor microenvironment, and immune responses. In a previous study, it was demonstrated that CD45 + IL11RA + cells were abundant in the spleen, while they constituted a rare subpopulation displaying mesenchymal morphology in the lungs of mice [17]. Moreover, IL11 signaling via IL11RA impacts cancer progression and immunomodulation, suppressing CD4 + T cell antitumor responses, offering potential for targeted therapy [16]. Interleukin (IL) 11 activates multiple intracellular signaling pathways by binding to cell surface receptors IL-11Rα and the β-subunit receptor, gp130. Dysregulated IL-11 signaling is associated with diseases like cancer and fibrosis. Recent research has elucidated the crystal structure of human IL-11Rα's extracellular domains, providing insights into IL-11 interaction [18], [19]. As our understanding of IL11RA's complex interactions within the tumor milieu deepens, it opens exciting possibilities for targeted therapeutic interventions aimed at modulating its activity to combat cancer's relentless advance.

This study investigates the therapeutic potential of mRNA-encoded IL11RA, aiming to harness its ability to modulate the tumor microenvironment and promote robust antitumor immunity. We present preclinical results focusing on intratumoral and intravenous delivery of mRNA encoding IL11RA, identified through iterative in vivo screening for potent antitumoral efficacy.