LUAD, the most frequent subtype of lung cancer, represents about 40 % of all lung cancer cases [1]. Despite the recent strides in surgical, radiation, and chemotherapeutic treatments, as well as their integrated use, the overall survival for LUAD patients has not significantly improved. The 5-year survival rate is still capped at 30 %, with no significant rise in the past few years [2]. The ongoing research into LUAD treatment has cast a spotlight on the tumor immune microenvironment and its pivotal role in LUAD progression. Immunotherapy, now a well-known therapeutic approach, hinges on augmenting the ability of immune cells to recognize tumor antigens for combating tumor cells [3]. Nonetheless, within the tumor microenvironment (TME), the debilitation of immune cells like natural killer (NK) cells and T lymphocytes (T cells) greatly hinder the effectiveness of immunotherapy [4]. Scholars are trying to find a solution to overcome this dysfunction of immune cells, therefore bolstering their tumor-killing capabilities in LUAD immunotherapy.

A decade-long follow-up study among a broad demographic revealed a clear association between decreased cytotoxicity of peripheral blood lymphocytes, such as NK cells, and a higher risk of cancer incidence [5]. NK cells are a subset of our innate immune cells, with the capacity to kill tumor cells. They can resist the invasion of viruses or tumor cells through cytotoxicity and cytokine release [6]. NK cells play a salient role in monitoring tumors, showing a strong, antigen-independent cytotoxic effect on abnormal cells, and regulate immunity by releasing cytotoxic granules that contain granzymes and perforin [7]. The diverse biological functions of NK cells in curbing cancer cell expansion and invasion have been noted, with impaired NK cell vitality being correlated with the malignant progression of diverse cancers [8]. Smad3 is found to expedite the progression of lung cancer by dampening the immune response of NK cells within the TME of mice. Delving deeper into the molecular mechanisms at play, researchers found that TGF-β1 reduces the expression of E4BP4 in NK cells originating from the bone marrow and spleen, in a process that depends on Smad3, thus dampening the antitumor immune reaction of these cells [9]. An elevated level of E4BP4 in NK cells is shown to foster their maturation and full functionality [10]. Moreover, the silencing of tumor suppressor genes also impacts the cytotoxic potency of NK cells against cancer. In 2022, Huang et al. [4] reported that NK cells forfeit their cytotoxic capabilities against LUAD cells in vitro when there is a mutation in the STK11 gene or a decrease in its expression levels. To sum up, NK cells are integral to the immune surveillance of tumors, and the study of their cytotoxic mechanisms against LUAD is sure to provide valuable information for LUAD immunotherapy.

MEX3A, identified as an RNA binding protein, possesses a conserved RNA binding domain alongside a C-terminal ring finger domain, which equips it to operate as an E3 ubiquitin ligase in catalyzing mRNA decay [11]. It has been implicated in the modulation of a spectrum of biological activities, such as embryogenesis, immune system functionality, and the initiation and progression of tumors [12]. MEX3A exerts an influence on tumor aggressiveness by mediating various signaling pathways [13]. Liang et al. [14] undertook a comprehensive functional analysis of MEX3A, deploying both in vitro and in vivo studies to confirm the role of MEX3A in fostering tumor cell proliferation, migration, invasion, and metastasis. Beyond this, they utilized four independent datasets from the Gene Expression Omnibus database to predict the implications of MEX3A expression alterations on signal activity in LUAD, highlighting that the ECM-receptor interaction pathway as being most notably affected. In addition to its role in tumor malignancy, MEX3A is thought to modulate immune responses. Recent research has shown that MEX3A is overexpressed in ovarian and non-small cell lung cancers and is inversely related to the infiltration levels of immune cells, including macrophages, neutrophils, B cells, and CD8+ T cells. These findings hint at a connection between MEX3A levels and the immune modulation within tumors [15,16] In light of this, we proposed that MEX3A might modulate immune functions in LUAD, and this research was set to clarify the molecular mechanisms at play.

We examined the effects of MEX3A expression levels on the cytotoxic activity of NK cells in LUAD and its regulatory mechanisms during LUAD progression. Our findings demonstrated that MEX3A, highly expressed in LUAD tissues and cells, diminishes NK cell cytotoxicity through the JAK2-STAT3 signaling pathway, and escalates the malignancy of LUAD.