Beyond the obvious: targeting the SLC transportome and non-canonical drug transport mechanisms in cancer therapy.

The solute carrier (SLC) superfamily comprises a broad array of membrane-bound transport proteins that are integral to the intracellular uptake of various substrates, including nutrients, endogenous metabolites, and an expanding repertoire of anticancer drugs. Although they play a pivotal role in drug disposition and pharmacokinetics, SLC-mediated influx mechanisms have historically garnered less research attention compared to the extensively studied ATP-binding cassette (ABC) efflux transporters. Increasing evidence now indicates that the expression profiles, functional activity, and regulatory pathways of SLC transporters critically influence intracellular drug accumulation, therapeutic outcomes, and the emergence of resistance in cancer. This review presents an in-depth analysis of key SLC transporters, such as organic cation transporters (OCTs), organic anion transporting polypeptides (OATPs), L-type amino acid transporter 1 (LAT1), and the cystine/glutamate exchanger(xCT), which have demonstrated relevance in mediating the uptake of anticancer agents. We explore their structural features, cancer-specific expression dynamics, and known interactions with chemotherapeutic and molecularly targeted therapies. Additionally, unconventional drug transport routes, including lipid raft-assisted endocytosis, exosome-mediated cargo transfer, and ion channel-facilitated uptake, are discussed as potential contributors to drug delivery in tumor cells. The review further explores innovative therapeutic strategies that aim to harness SLC transporters for clinical benefit, including prodrug designs, nanoparticle-based delivery systems, and transporter-directed drug development. Clinical progress in targeting LAT1, xCT, and OATP family members is also reviewed, with a focus on ongoing trials. Finally, we address the current limitations in targeting SLCs, such as overlapping substrate specificity, tumor-specific heterogeneity, and interindividual genetic variations affecting transporter function. By framing SLCs as viable and strategic targets within the oncology drug development landscape, this review highlights their emerging potential in shaping future precision oncology initiatives.