SLC39 and SLC30 zinc transporters: functions and potential mechanisms in cancer

Abstract

Solute carrier (SLC) transporters are membrane proteins that facilitate the movement of various substrates, such as nutrients and organic or inorganic ions, across cellular membranes. Recent studies underscore the critical roles of SLC transporters in regulating cancer metabolism, immune evasion, and the tumor microenvironment. Increasing evidence suggests that the SLC39 and SLC30 families of zinc transporters, responsible for importing and exporting zinc into and out of the cytoplasm, respectively, modulate intracellular zinc distribution and signaling and may play a role in cancer initiation or progression. In this review, we discuss the functional roles of these zinc transporters in different cancer types and examine potential mechanisms linking zinc metabolism with oncogenic pathways that contribute to malignancy.

INTRODUCTION

Zinc is an essential micronutrient that must be obtained through external sources to maintain adequate levels within the body (1). It is the second most abundant trace element in the human body after iron and serves as a cofactor for approximately 10% of all proteins. More than 300 enzymes and 1,000 transcription factors depend on zinc for their activity; accordingly, zinc is involved in diverse enzymatic and metabolic functions, including DNA and protein synthesis, cellular proliferation and differentiation, and mitosis (2). Unlike redox-active metals such as iron or copper, zinc mainly acts as a stable cofactor, and dynamic changes in the labile zinc pool can serve as second messengers that influence multiple cellular processes.

Strict control of intracellular zinc concentration is essential, since both zinc deficiency and overload disrupt cellular homeostasis. Zinc homeostasis is maintained through the regulation of zinc fluxes across biological membranes, sequestration of free zinc by metallothionein, and storage in specific cellular organelles such as vesicles (3). As zinc cannot pass through cellular membranes by diffusion, its distribution relies on the orchestrated activities of two transporter families within the solute carrier (SLC) superfamily: SLC39 and SLC30 zinc transporters. These two transporter families function antagonistically to maintain zinc balance. The SLC39 family, which encodes Zrt- and Irt-like (ZIP) proteins, mediates zinc influx into the cytoplasm from either the extracellular space or intracellular compartments. In contrast, the SLC30 family, encoding ZnT proteins, facilitates zinc efflux from the cytoplasm to the extracellular space or into the lumen of organelles.

A growing body of research has associated specific zinc transporters with cancer phenotypes across a range of cancer types. Despite numerous studies indicating the prognostic significance of zinc transporters in cancer, mechanistic investigations that clarify the functional roles of these zinc transporters and their associated downstream signaling pathways in cancer remain limited (4, 5). In the following sections, we examine the roles of SLC39 and SLC30 family transporters in cancer, focusing on evidence from functional studies. Additionally, we explore putative mechanisms by which zinc metabolism, regulated by these transporters, may influence tumorigenesis and the remodeling of the tumor microenvironment (TME).

RESULTS

SLC39 zinc transporters in cancer

In humans, 14 members of the SLC39 family (SLC39A1-14, also referred to as ZIP1-14) have been identified, exhibiting diverse tissue distributions and unique physiological roles (6). These transporters facilitate an increase in cytosolic zinc by mediating zinc influx from the extracellular space or from intracellular compartments such as the Golgi apparatus, ER, or lysosomes. Each ZIP protein contains eight transmembrane domains, with conserved histidine residues located within transmembrane domains 4 and 5 that are essential for zinc transport, while the N- and C-termini of ZIP proteins are either exposed to the extracellular space or reside within the lumen of intracellular organelles. The SLC39 family is divided into four subfamilies based on sequence homology: subfamily I (SLC39A9); subfamily II (SLC39A1, 2, and 3); the LIV-1 subfamily (SLC39A4, 5, 6, 7, 8, 10, 12, 13, and 14); and the gufA subfamily (SLC39A11). In the subsequent discussion, we will review studies that have elucidated functional mechanisms related to cancer for each of these family members (Table 1).

Table 1.

Functions of SLC39 zinc transporters in cancer

Gene	Cancer type	Manipulation	In vitro effects	In vivo effects	Ref
SLC39A1	Hepatocellular carcinoma	shRNA	Proliferation, migration, invasion ↓	-	(10)
		shRNA, Cre lox KO, Inhibiting peptide	Proliferation, autophagy, DRP1 ↓	Tumor growth, autophagy ↓	(11)
	Prostate cancer	cDNA overexpression	NF-κB activity ↓ IL-6, IL-8, Bcl-2, Bcl-XL ↓	Tumor growth with zinc-enriched diet ↓	(9)
SLC39A4	Esophageal squamous cell carcinoma	siRNA	Proliferation, migration, invasion, EMT marker ↓ Cisplatin-induced apoptosis and sensitivity ↑	-	(23)
		cDNA overexpression	Proliferation, migration, invasion ↑ Cisplatin-induced apoptosis ↓	-
	Glioblastoma	CRISPR KO	-	Tumor growth ↓ Mouse survival ↑	(35)
		cDNA overexpression	-	Tumor growth ↑ Mouse survival↓
	Hepatocellular carcinoma	siRNA	Cell cycle, migration ↓	-	(24)
		shRNA	Migration, invasion ↓	-	(25)
		cDNA overexpression	Migration, invasion ↑	-
	Nasopharyngeal carcinoma	shRNA	Migration, invasion, EMT marker ↓ Radiotherapy sensitivity ↑	Metastasis ↓ Radiotherapy sensitivity ↑	(32)
		cDNA overexpression	Migration, invasion, EMT marker ↑	-
	Non-small cell lung cancer	shRNA	Proliferation, migration, EMT marker ↓	Pulmonary metastasis ↓	(21)
		shRNA, CRISPR KO	Migration, invasion ↓	Metastasis ↓	(22)
		cDNA overexpression	Migration, invasion ↑	Metastasis ↑
	Ovarian cancer	shRNA, CRISPR KO	Proliferation ↓	Tumor growth, metastasis ↓ Mouse survival ↑	(30)
		cDNA overexpression	Proliferation ↑	Tumor growth, metastasis ↑ Mouse survival↓
	Pancreatic cancer	cDNA overexpression	Proliferation under serum starvation ↑	Tumor growth, dissemination ↑	(18)
		shRNA	Proliferation, migration, invasion ↓	Tumor growth ↓	(19)
		shRNA	Migration, invasion ↓	-	(28)
		shRNA	Extracellular vesicles ↓	Muscle wasting, cachexia ↓	(33)
SLC39A5	Esophageal squamous cell carcinoma	shRNA	Proliferation, migration, invasion ↓	-	(38)
		shRNA	-	Tumor growth ↓	(39)
	Gastric cancer	shRNA	Proliferation, migration, invasion ↓	Tumor growth ↓	(40)
	Lung cancer	cDNA overexpression	Proliferation, pAKT ↑	-	(41)
		shRNA	Proliferation, pAKT ↓	Tumor growth ↓
SLC39A6	Esophageal squamous cell carcinoma	siRNA	Proliferation, migration, invasion ↓	-	(50)
		siRNA	Proliferation, invasion, EMT marker ↓	-	(51)
		shRNA	Proliferation, migration, invasion ↓	Tumor growth, metastasis ↓	(52)
		cDNA overexpression	Proliferation, migration, invasion ↑	-
	Pancreatic cancer	siRNA	Proliferation, migration, EMT marker ↓	Tumor growth ↓	(53)
	Hepatocellular carcinoma	siRNA	Migration, invasion, EMT marker ↓	-	(54)
		siRNA	Proliferation, migration, invasion ↓	Tumor growth ↓	(55)
	Gastric cancer	siRNA	Proliferation, migration, invasion↓	-	(56)
SLC39A7	Colorectal cancer	shRNA	Proliferation ↓Apoptosis ↑	-	(63)
	Hepatocellular carcinoma	Inhibitor	Proliferation, migration, invasion ↓ Apoptosis ↑	Tumor growth ↓	(67)
	Cervical cancer	shRNA	Proliferation, migration, invasion ↓ Apoptosis ↑	-	(64)
SLC39A8	Esophageal squamous cell carcinoma	shRNA, inhibitor	Proliferation ↓Ferroptosis ↑	Tumor growth ↓	(76)
		cDNA overexpression	Proliferation ↑	-
	Neuroblastoma	shRNA	Proliferation, migration ↓	-	(75)
	Clear cell renal cell carcinoma	siRNA	Proliferation, migration, invasion ↑	-	(77)
		cDNA overexpression, ZnCl2 treatment	Proliferation, migration, invasion ↓	-
SLC39A10	Breast cancer	siRNA	Migration ↓	-	(83)
	Gastric cancer	siRNA, shRNA	Proliferation, MAPK/PI3K signaling ↓	-	(84)
		cDNA overexpression	Proliferation, MAPK/PI3K signaling ↑	Tumor growth ↑
	Hepatocellular carcinoma	shRNA	Proliferation, migration ↓ Apoptosis ↑	-	(88)
	Osteosarcoma	shRNA	Proliferation, MAPK/PI3K signaling ↓	Tumor growth ↓	(85)
		cDNA overexpression	MAPK/PI3K signaling ↑	Tumor growth ↑
SLC39A11	Cervical cancer	shRNA	Proliferation, migration, invasion ↓	-	(92)
	Pancreatic cancer	siRNA	Proliferation, MAPK signaling ↓	-	(91)
SLC39A13	Ovarian cancer	CRISPR KO	Proliferation, migration, invasion, adhesion ↓	Metastasis ↓	(96)
SLC39A14	Breast cancer	KO mouse	-	Muscle wasting ↓	(99)
	Nasopharyngeal carcinoma	shRNA	Proliferation ↓	Tumor growth ↓ CD8＋ T cell infiltration ↑	(100)

The prostate typically accumulates the highest concentrations of zinc in the body and, as a result, has been extensively investigated regarding zinc transporter functions (7). SLC39A1 expression is downregulated in prostate cancer and is associated with zinc depletion, indicating that prostate cancer cells lose the capacity to accumulate zinc as malignancy progresses (8). Ectopic expression of SLC39A1 in prostate cancer cells suppressed NF-κB activity and reduced protumorigenic cytokine expression, resulting in decreased tumor growth in mice maintained on a zinc-enriched diet, which supports a tumor-suppressive role for SLC39A1 (9). In contrast, in other malignancies such as hepatocellular carcinoma (HCC), SLC39A1 depletion led to impaired cell proliferation, migration, and invasion, implying a protumorigenic function of SLC39A1 in this context (10). Moreover, SLC39A1 was overexpressed in patients with relapsed HCC, where it promoted autophagy and mitochondrial fission by interacting with dynamin-related protein 1 (11, 12). Notably, a recent study identified SLC39A1 expression within a subset of fibroblasts, characterized by single-cell RNA sequencing, that was markedly enriched in mouse lung tumors following doxorubicin administration (13). These fibroblasts were shown to facilitate zinc transfer to cancer cells through gap junctions, promoting chemoresistance, thereby highlighting the role of stromal cell zinc metabolism in modulating intercellular communication with tumor cells and its influence on chemotherapy response. SLC39A2 and SLC39A3, which comprise subfamily II along with SLC39A1, have received limited attention in cancer research. Evidence indicates that both transporters are downregulated in prostate cancer, and SLC39A3 is also reduced in pancreatic cancer, although the relationship of these findings to other zinc transporters and the broader zinc metabolic network warrants further investigation (14, 15).

SLC39A4, a member of the LIV-1 subfamily, was initially identified as a gene responsible for acrodermatitis enteropathica, a genetic disorder characterized by zinc deficiency, and has since been extensively investigated in the context of cancer (16). Consistent with other transporters mentioned previously, the expression of SLC39A4 is also reported to be downregulated in prostate cancer (17). Nevertheless, in various other cancer types, SLC39A4 generally exhibits protumorigenic activity. Specifically, in pancreatic cancer, SLC39A4 is overexpressed in pancreatic adenocarcinoma tissues, and its overexpression enhances tumor growth in both subcutaneous and orthotopic xenograft models, in addition to facilitating peritoneal dissemination and ascites formation in mice (18). Furthermore, depletion of SLC39A4 suppresses pancreatic tumor growth and prolongs the survival of mice bearing tumors (19). Subsequent investigations have shown that SLC39A4-driven signaling promotes pancreatic cancer progression through inhibition of genes including TP53INP1, LATS2, and CD44 (20). SLC39A4 has also been demonstrated to be overexpressed in non-small cell lung cancer (NSCLC), where it facilitates proliferation and metastasis via activation of the Snail-N-cadherin pathway (21, 22). In esophageal squamous cell carcinoma (ESCC), SLC39A4 expression is notably high, and silencing of SLC39A4 results in reduced proliferation and impaired cellular motility, as well as increased sensitivity to cisplatin treatment (23). Evidence also indicates that SLC39A4 is essential for cell migration and invasiveness in HCC, and contributes to tumor recurrence following liver transplantation (24, 25). Mechanistically, SLC39A4 promotes the expression of zinc finger E-box binding homeobox 1 (ZEB1) (26) and further activates the IL-6/STAT3 signaling pathway via the zinc finger transcription factor cAMP response element-binding protein (CREB) (27). SLC39A4 can also increase ZEB1 expression through mechanisms that do not involve CREB, resulting in the downregulation of ZO-1 and claudin-1 (28). SLC39A4 regulates yes-associated protein 1 (YAP1), which forms a complex with ZEB1 to activate the adhesion molecule ITGA3 (29). In ovarian cancer, SLC39A4 modulates both in vitro proliferation and in vivo tumor growth, and also enhances self-renewal capacity through the NOTCH3 pathway (30, 31). While SLC39A4 is most frequently reported to regulate cancer cell proliferation, migration, and/or invasion, emerging evidence indicates its role in chemoresistance via equilibrative nucleoside transporter 1 (ENT1), which mediates cellular uptake of chemotherapeutic agents such as gemcitabine (26). Inhibition of SLC39A4 has also been shown to reverse epithelial-mesenchymal transition (EMT) and to enhance radiosensitivity in nasopharyngeal carcinoma (32). SLC39A4 has a distinct role in cancer-associated cachexia, where it promotes muscle wasting and cachexia in mice with orthotopic pancreatic tumors via RAB27B-mediated release of extracellular vesicles (33, 34). Within the TME, SLC39A4 enhances microglial plasticity mediated by extracellular vesicles carrying triggering receptor expressed on myeloid cells-1 (TREM1), thereby facilitating tumor progression (35). Additionally, although the structures of numerous zinc transporters remain unresolved, the crystal structure of human SLC39A4 has identified the extracellular domain critical for optimal zinc transport (36, 37).

SLC39A5, another member of the LIV-1 subfamily, has been shown to have a protumorigenic role in multiple cancer types. SLC39A5 is highly expressed in esophageal cancer tissues, and loss of this transporter reduced cell proliferation, migration, and invasion both in vitro and in vivo (38, 39). SLC39A5 expression is also upregulated in gastric cancer and lung adenocarcinoma (LUAD), where it enhances proliferation, migration, and invasion, in association with activation of the PI3K/AKT signaling pathway (40, 41). Additional important functional mechanisms of SLC39A5 have been elucidated in non-cancer contexts. Recently generated mice lacking Slc39a5 demonstrated protection under conditions of metabolic stress, including congenital or diet-induced obesity and non-alcoholic steatohepatitis (NASH) (42). These effects are partially attributable to the inhibition of protein phosphatases and the activation of AMPK and AKT signaling, indicating a possible role in regulation of tumorigenesis. SLC39A5 also contributes to venous angiogenesis by maintaining systemic zinc homeostasis, as it removes excess zinc from the body; loss of this function leads to systemic zinc accumulation, delayed sprouting, and impaired endothelial cell migration (43). Both SLC39A4 and SLC39A5 serve vital functions in the intestine and are implicated in pathological states, highlighting the need for further investigation in cancers arising from intestinal tissues (44). Moreover, in the ovary, SLC39A5 expression is induced by an endocrine-disrupting chemical, subsequently leading to NF-kB pathway activation and pyroptosis (45).

SLC39A6, previously known as LIV-1, was firstly characterized as an estrogen-responsive gene (46) and is capable of forming a heteromeric complex with SLC39A10 to induce EMT by promoting the nuclear localization of the zinc-finger transcription factor Snail (47). The interaction between SLC39A6 and SLC39A10, initially discovered during zebrafish gastrulation, is also present in mammalian cells and is implicated in the regulation of mitosis (48, 49). Genome-wide association studies have shown that SLC39A6 expression increases progressively in ESCC samples and is associated with poorer survival in ESCC, mediated by enhanced proliferation, migration, and invasion of ESCC cells (50, 51). Another independent study found that SLC39A6 controls the expression of genes related to cellular aggressiveness, including MMP-1, MMP-3, MYC, and SLUG in ESCC cells (52). Additionally, in PDAC, HCC, and gastric cancer, the depletion of SLC39A6 resulted in impaired proliferation both in vitro and in vivo, as well as reduced migration and lower levels of EMT markers (53-56). The metabolic consequences of SLC39A6 loss have also been examined, revealing that both SLC39A6 and SLC39A10 are upregulated in liver cancer and that SLC39A6 depletion led to increased levels of electron transport chain-associated metabolites such as acetyl-CoA, citrate, isocitrate, α-ketoglutarate, NADH, and ATP (57). The expression of mitochondrial respiratory chain genes, including COX17 and NDUFS3, was found to be upregulated in SLC39A6-depleted cells. Moreover, SLC39A6 is essential for normal T cell development in zebrafish, indicating a plausible role in modulating immune responses in cancer (58, 59). In terms of therapeutic strategies, multiple antibody-drug conjugate drugs targeting SLC39A6 have been developed and assessed in cancer cells, but their clinical effectiveness and underlying mechanisms remain to be clarified (60).

SLC39A7 is a member of the LIV-1 subfamily that localizes to the membranes of organelles, such as the Golgi apparatus or ER, where it facilitates zinc transport into the cytoplasm (61). Zinc transport mediated by SLC39A7 has been demonstrated to promote growth factor signaling in tamoxifen-resistant breast cancer cells, and loss of SLC39A7 impedes proliferation while inducing apoptosis in colorectal and cervical cancer cells (62-64). SLC39A7 has also been implicated in the resolution of ER stress, which supports intestinal epithelial self-renewal; however, the relevance of this function in cancer remains unexplored (65). In addition, a Notch pathway screening identified the SLC39A7 inhibitor NVS-ZP7, which triggers apoptosis and ER stress in leukemia cells, and has been evaluated in HCC models to suppress tumorigenesis and enhance apoptosis in vivo (66, 67). Consistent with the function of SLC39A7 as a gatekeeper for zinc release from intracellular organelle stores, SLC39A7 has been shown to be regulated through phosphorylation by kinases such as CK2 (68). The release of zinc by SLC39A7 can activate numerous downstream kinases, contributing to MAPK, PI3K, and mTOR signaling pathways (69, 70). Notably, recent data indicate that SLC39A7 modulates ferroptosis, an iron-dependent form of cell death, through the maintenance of ER homeostasis (71). This suggests there may be significant crosstalk between zinc and iron signaling, and further research could uncover additional mechanisms linking the signaling of various metals. Moreover, SLC39A7 has been implicated in mitophagy repression by preventing the accumulation of PINK1 and Parkin in mitochondria (72).

SLC39A8, a member of the LIV-1 subfamily, functions as a multifunctional transporter that mediates the influx of metals, including zinc, iron, and cadmium (73, 74). Depletion of SLC39A8 in neuroblastoma cells resulted in reduced proliferation and migration (75). Similarly, SLC39A8 was upregulated in ESCC samples, and its depletion suppressed proliferation (76). Mechanistically, the loss of SLC39A8 decreased the levels of ferritin light chain (FTL), ferritin heavy chain (FTH1), and glutathione peroxidase 4 (GPX4), which are associated with ferroptosis. This study also identified a novel SLC39A8 inhibitor, Nobiletin, which was shown to induce ferroptosis and inhibit proliferation. In contrast, SLC39A8 expression decreased progressively in clear cell renal cell carcinoma (ccRCC), and overexpression of SLC39A8 suppressed proliferation, migration, and invasion, though the underlying mechanisms remain unclear (77). This inhibitory effect is similar to the effects of SLC39A1 overexpression in prostate cancer and may be related to the fact that both the prostate and kidney have high requirements for zinc but warrants further investigation. Additionally, SLC39A8 modulates zinc influx in human monocytes and macrophages to activate mTORC1 signaling and the inflammatory response; however, its role in regulating immune cells within the TME has not been yet investigated (78).

SLC39A9 is the only member of subfamily I and is notable for its distinctive ability to interact with testosterone (79). This interaction promotes melanoma cell proliferation via MAPK and YAP signaling, and the FDA-approved androgen receptor inhibitor bicalutamide, repurposed to target SLC39A9, significantly inhibited the growth of SLC39A9-expressing tumors in male, but not female, mice (80). These findings suggest that SLC39A9 may play a crucial role in male melanoma patients, and further studies should determine whether SLC39A9 is activated by testosterone or other hormones in different cancer types. In a recent study, SLC39A9 was discovered through a CRISPR screen focused on glycan regulation in which knockout of SLC39A9 induced changes in O- and N-glycan expression due to zinc accumulation in the secretory pathway (81). As alterations in glycosylation are common in cancer, investigating the potential of zinc transporters as therapeutic targets or biomarkers linked to glycosylation changes is a compelling area for future research (82).

SLC39A10 is a member of the LIV-1 subfamily and has been shown to exhibit protumorigenic functions in various contexts. SLC39A10 forms a complex with SLC39A6 as previously described; however, in some settings, SLC39A10 mediates cellular effects independently, such as promoting breast cancer cell migration (83). Enhanced expression of SLC39A10 has been detected in both gastric cancer and osteosarcoma cells, where it facilitates increased MAPK and PI3K signaling (84, 85). In gastric cancer cells, SLC39A10 was found to be a direct transcriptional target of c-Myc, establishing a feedback regulatory loop, while in B cells, its expression is controlled by the JAK-STAT pathway (86). Upregulation of SLC39A10 was also observed in malignant blasts of acute myeloid leukemia (AML), and antibody-mediated targeting of SLC39A10 led to impaired zinc uptake and reduced cell proliferation (87). In HCC cells, higher SLC39A10 expression correlated positively with tumor-infiltrating lymphocytes and immune checkpoints such as cytotoxic T-lymphocyte associated protein 4 (CTLA4) and T-cell immunoglobulin and mucin domain-containing 3 (TIM3) (88). SLC39A10 has also been recognized as a principal zinc importer in macrophages, where it plays a role in activating these cells and enhancing cytokine expression, indicating that SLC39A10 may modulate multiple elements within the TME (89). Additionally, SLC39A10 is crucial for embryonic hematopoiesis and is essential for hematopoietic stem cell (HSC) survival under zinc-deficient conditions (90). Collectively, these data suggest that SLC39A10 functions as a survival factor for HSCs, and future studies should determine whether this mechanism is relevant to hematologic cancers.

SLC39A11 is the only known member of the GufA subfamily and its role in cancer biology has been only minimally explored. Elevated SLC39A11 expression correlates with poor prognosis in pancreatic cancer, and silencing SLC39A11 inhibits pancreatic cancer cell proliferation (91). Additional research using cervical cancer cell models found that SLC39A11 is required for cell proliferation, migration, invasion, and regulation of mitochondrial membrane potential (92).

SLC39A12 and SLC39A13 are members of the LIV-1 subfamily and have not been extensively investigated in the context of cancer. SLC39A12 has been examined primarily in relation to the nervous system and the pulmonary vascular response under hypoxic conditions (93, 94). SLC39A13, which predominantly localizes to vesicular membranes, has been linked to a hereditary connective tissue disorder characterized by mutations that cause zinc deficiency in the ER due to sequestration of zinc within vesicular compartments (95). Furthermore, SLC39A13 has been identified as an independent prognostic marker in ovarian cancer and shown to be essential for metastasis (96). In contrast, SLC39A13 expression is decreased in fibrosarcoma, a skin tumor subtype, where loss of SLC39A13 results in suppression of autophagy (97).

SLC39A14, the final member of the LIV-1 subfamily, has been well characterized regarding its physiological roles, and it facilitates the transport of multiple metals with distinct affinities, including iron, cadmium, manganese, and zinc (98). Despite this, there are only a limited number of studies exploring its specific function within oncogenic processes. In one report, SLC39A14 was found to mediate cancer-associated cachexia (99). Examination of cachectic muscle tissues from metastatic animal models showed a unique and marked upregulation of SLC39A14 among SLC39 family members, contributing to muscle wasting. Additionally, SLC39A14 was found to be transcriptionally upregulated by SOX4, which enhanced the proliferation and clonogenicity of cancer cells while reducing T cell effector function in nasopharyngeal carcinoma (100). These findings highlight the role of zinc, mediated by zinc transporter function, in remodeling both the metabolic pathways in cancer cells and the overall metabolic milieu of the TME.

SLC30 zinc transporters in cancer

The SLC30 family, classified within the cation diffusion facilitator (CDF) family of proteins, comprises 10 members. The majority of SLC30 transporters, commonly referred to as ZnT proteins, are localized to organellar membranes, and their physiological as well as pathological roles are discussed extensively in other reviews (101). Based on protein sequence analysis, SLC30 transporters are divided into four subfamilies: subfamily I (SLC30A5 and 7), subfamily II (SLC30A2, 3, 4, and 8), subfamily III (SLC30A1 and 10), and subfamily IV (SLC30A6 and 9). In contrast to the well-characterized functions of SLC39 family members, functional data on SLC30 transporters in cancer remain limited. This is most likely due to the fact that many SLC30 transporters are localized to intracellular organelles, such as Golgi apparatus, endosomes, lysosomes, and mitochondria, making it inherently difficult to measure their transport activity. Furthermore, technical limitations in assessing zinc flux such as the scarcity of reliable organelle-targeted zinc probes have constrained the functional characterization of SLC30-mediated transport. Nonetheless, we describe the currently known functional roles of SLC30 family members in cancer (Table 2).

Table 2.

Functions of SLC30 zinc transporters in cancer

Gene	Cancer type	Manipulation	In vitro effects	In vivo effects	Ref
SLC30A1	Bladder cancer	siRNA	Proliferation ↓	-	(105)
SLC30A2	Breast cancer	cDNA overexpression	Invasion ↓	-	(110)
SLC30A10	Colon cancer	cDNA overexpression	Proliferation, migration ↓	-	(115)
		shRNA	Proliferation, migration ↑	-

SLC30A1, which belongs to subfamily III, acts predominantly as the main zinc exporter on the plasma membrane by transporting zinc ions from the cytoplasm into the extracellular space, whereas other SLC30 family members are primarily associated with intracellular organellar membranes (102). Complete knockout of SLC30A1 in mice is embryonically lethal, underscoring its critical role in systemic zinc homeostasis (103). In the context of prostate cancer, SLC30A1, SLC30A9, and SLC30A10 are upregulated, while SLC30A5 and SLC30A6 exhibit decreased expression (104). In contrast, SLC30A1 expression is higher in bladder cancer tissue compared to adjacent non-tumorous tissue, and its expression correlates with TNM stage (105). In this setting, SLC30A1 depletion led to a modest reduction in proliferation, which was associated with decreased cyclin D1 levels. More recently, SLC30A1 was also identified as a transporter capable of importing copper, and this function is required for copper-induced cell death, known as cuproptosis (106). Future studies should investigate the role of SLC30A1 in conjunction with its substrates within specific oncogenic contexts (107).

The following studies investigate the functions of three subfamily II members: SLC30A2, SLC30A3, and SLC30A4. SLC30A2, together with SLC30A1, SLC30A9, and SLC30A10, shows increased expression in prostate adenocarcinoma (108). Conflicting findings have been reported in two studies examining SLC30A2 in breast cancer. One study found that overexpressing SLC30A2 in MDA-MB-453 breast cancer cells significantly reduced invasion, whereas another study demonstrated that SLC30A2 depletion in T47D breast cancer cells triggered lysosomal swelling and apoptosis (109, 110). Additional research is necessary to clarify the molecular role of SLC30A2 in breast cancer. Expression of SLC30A3, which regulates vesicular zinc in presynaptic terminals, is diminished in paclitaxel-treated mice, but corresponding evidence in human cancer remains unreported (111). Considering that resistance to chemotherapy poses a major challenge in cancer treatment, understanding the behavior of zinc transporters during and after administration of anti-cancer therapies is crucial. Regarding SLC30A4, its expression declines during progression from early prostate disease to invasive prostate cancer (112).

Among the remaining SLC30 family members, SLC30A8 has been demonstrated to facilitate zinc uptake into insulin secretory granules within pancreatic islet β cells, and polymorphisms in SLC30A8 are correlated with a decreased risk of type 2 diabetes in humans (113). SLC30A9 has been shown to regulate mitochondrial zinc concentrations to support mitochondrial homeostasis (114). Future studies should determine whether these SLC30 transporter functions also play a role in cancer. As for SLC30A10, expression is reduced in colorectal cancer tissues and cell lines, and its overexpression leads to decreased proliferation and migration (115). The precise activity of certain zinc transporters is essential for the correct activation of zinc-dependent ectoenzymes through zinc metalation. For example, the cancer-associated ectoenzymes autotaxin, matrix metalloproteinase 9, and carbonic anhydrase IX depend on a combination of SLC30A5-SLC30A6 heterodimer activity, SLC30A7 homodimer, or SLC30A4 homodimer for their function (116). Collectively, these findings indicate that the activities of SLC30 family transporters remain insufficiently characterized in the context of cancer and highlight the need for additional research.

DISCUSSION

In this review, we examine the established roles of SLC39 and SLC30 zinc transporters in cancers. SLC transporters are recognized as some of the most understudied proteins considering the size of their family, and numerous aspects of their biology are still not well understood (117). SLC transporters have attracted growing attention as drug targets, and advancing our understanding of their biological functions will facilitate the development of novel therapeutic approaches (118). Despite significant advances in identifying the functions of these transporters, our comprehension of how SLC39 and SLC30 transporters are integrated into the broader context of cancer biology is still limited. Many investigations of SLC39 and SLC30 transporters predominantly focus on prognostic analyses, and although some studies have provided insights into their cellular and molecular mechanisms in cancer cells, much of this research remains centered on proliferation, migration, and invasion phenotypes (119). Zinc is capable of binding to cysteine residues, thereby influencing protein function, and recent investigations have reported multiple cysteine sites throughout the human proteome that interact with zinc (120). Given that zinc regulates a broad array of cellular processes, it is crucial to elucidate the precise mechanisms of these transporters for the development of targeted therapies and to translate this knowledge to benefit specific patient populations (1, 121, 122).

In this section, we would also like to highlight several intriguing questions that remain for future research. First, zinc is stored in various organelles, including the mitochondria, lysosome, ER, nucleus, and the cytoplasm, and its transport among these organelles likely plays a crucial biological role. Recent studies have demonstrated that the release of zinc from the lysosome into the cytosol, which is regulated by mucolipin-1, also known as TRPML1, can influence the fusion between autophagosomes and lysosomes (123). Furthermore, in Caenorhabditis elegans intestinal cells, a lysosome-related organelle has been found to contain an expandable compartment that facilitates rapid changes in zinc transporter composition to mediate homeostasis during either zinc overload or deficiency (124). Although the majority of SLC39 transporters are believed to be located at the plasma membrane, several family members are localized to membranes other than that of the plasma membrane; for instance, SLC39A7 resides in the Golgi apparatus and ER, while SLC39A13 is found in the Golgi apparatus and cytoplasmic vesicles (95, 125). In the case of SLC30 transporters, aside from SLC30A1, most SLC30 members are suggested to localize to vesicular membranes. Further research is warranted to elucidate the molecular mechanisms underlying zinc dynamics and to identify the transporters involved in these processes, and recent advances in imaging zinc in multiple organelles could facilitate progress in these investigations (126).

Second, elucidating the role of zinc metabolism and its associated transporters in modulating and remodeling the TME is of considerable importance. Recent findings indicate that intracellular zinc confers protection to cancer cells against T cell-mediated cytotoxicity (127). This protection occurs as intracellular zinc inhibits TNF-mediated cell death by stabilizing inhibitor of apoptosis proteins, highlighting a promising targetable vulnerability. Moreover, a recent preprint reported that Cdkn2a^low tumors, which are refractory to anti-PD1 and anti-PD-L1 therapies, exhibit significantly reduced zinc levels and that SLC39A9 mediates anti-PD1 resistance (128). Macrophage-mediated mechanisms underlie this effect, with Cdkn2a^low tumor cells depleting macrophage zinc within the TME, thereby impairing their phagocytic function. Additionally, SLC39A4-overexpressing tumors have been shown to produce increased levels of IL-6 and IL-10 in the TME, which may contribute to microenvironmental remodeling (35). Zinc not only directly regulates cancer cell metabolism and signaling but also modulates the functional activity of immune and stromal cells (129, 130), indicating that SLC39 and SLC30 zinc transporters could play crucial roles in regulating immune evasion within the TME. Although these studies have demonstrated the important function of zinc and its transporters in specific contexts, future research adopting integrative, multi-scale approaches, such as spatial and single-cell transcriptomics or imaging mass spectrometry, will enable a deeper understanding of how zinc influx and efflux balance operates within cancer cells and the TME.

Lastly, although post-translational modifications of SLC39 and SLC30 zinc transporters are likely relevant in cancer, this area remains underexplored. For example, SLC39A7 has been identified as being phosphorylated at multiple residues, with downstream MAPK, PI3K, and mTOR signaling pathways being regulated by these modifications (70). Future research should address whether other members of the SLC39 or SLC30 family are similarly regulated through post-translational modifications and the consequences for downstream phenotypes. Further investigation into SLC39 and SLC30 transporters in cancer is certain to clarify the complex roles of zinc metabolism in oncogenesis and lead to new therapeutic strategies.