BACKGROUND: The tumor microenvironment (TME) is a major obstacle to effective cancer therapy, driving tumor progression, metastasis, and resistance to conventional treatments. Mesenchymal stem cells (MSCs) have attracted increasing interest as therapeutic vehicles due to their intrinsic tumor-homing capability; however, the therapeutic efficacy of unmodified MSCs remains limited. METHODS: This review examines recent engineering strategies for enhancing MSC therapeutic functionality in TME modulation and precision cancer therapy. Relevant literature was surveyed with focus on nanotechnology-enabled approaches. We analyze key TME features including hypoxia, immunosuppression, and physical barriers, and how various engineering strategies address these challenges. RESULTS: Engineered MSCs have been successfully transformed into therapeutic "bio-factories" through genetic modification, enabling sustained secretion of cytokines, enzymes, or therapeutic proteins. In parallel, payload-based strategies have established MSCs as effective "Trojan horse" carriers for nanomaterials, chemotherapeutic agents, and oncolytic viruses, allowing precise delivery and active remodeling of the TME. These approaches collectively enhance tumor targeting, therapeutic efficacy, and spatial control within solid tumors. CONCLUSION: The integration of MSC biology with nanotechnology provides a powerful platform for regulating the TME and achieving precision oncology. While challenges related to safety, protumorigenic effects, and manufacturing scalability remain, recent advances are rapidly addressing these barriers. Engineered MSC-based therapies hold great promise to revolutionize cancer treatment and overcome the longstanding challenges of solid tumor therapy.

Chimeric antigen receptor natural killer (CAR-NK) cell therapy has emerged as a promising immunotherapeutic modality with potent cytotoxicity and a favorable safety profile. However, its therapeutic efficacy is often limited by poor infiltration into tumors and the profoundly immunosuppressive tumor microenvironment (TME). In hepatocellular carcinoma (HCC), one of the leading causes of cancer-related mortality, this suppressive TME severely compromises the function of CAR-NK cells. To overcome this limitation, we developed a combinatorial strategy integrating irreversible electroporation (IRE), a clinically approved nonthermal ablation modality capable of reshaping the TME, with glypican-3 (GPC3)-targeted CAR-NK cells generated via 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-functionalized lipid nanoparticle (LNP)-mediated gene delivery. IRE promoted immunogenic cell death and reprogrammed the TME through the release of damage-associated molecular patterns and chemokines, notably CX3CL1, thereby enhancing NK cell infiltration. Moreover, IRE-treated HCC cells exhibited heightened susceptibility to NK-mediated cytotoxicity through elevated intracellular reactive oxygen species, establishing a mechanism of immune sensitization. When combined with LNP-engineered GPC3-specific CAR-NK cells, this approach elicited synergistic antitumor activity, as demonstrated by superior tumor lysis in vitro and robust tumor regression in various HCC models without systemic toxicity. By coupling TME remodeling of IRE with the precision and safety of LNP-engineered CAR-NK cells, we propose a durable, clinically actionable treatment paradigm to overcome resistance in solid tumors, such as HCC.

BACKGROUND: The tumor microenvironment (TME) is a major obstacle to effective cancer therapy, driving tumor progression, metastasis, and resistance to conventional treatments. Mesenchymal stem cells (MSCs) have attracted increasing interest as therapeutic vehicles due to their intrinsic tumor-homing capability; however, the therapeutic efficacy of unmodified MSCs remains limited. METHODS: This review examines recent engineering strategies for enhancing MSC therapeutic functionality in TME modulation and precision cancer therapy. Relevant literature was surveyed with focus on nanotechnology-enabled approaches. We analyze key TME features including hypoxia, immunosuppression, and physical barriers, and how various engineering strategies address these challenges. RESULTS: Engineered MSCs have been successfully transformed into therapeutic "bio-factories" through genetic modification, enabling sustained secretion of cytokines, enzymes, or therapeutic proteins. In parallel, payload-based strategies have established MSCs as effective "Trojan horse" carriers for nanomaterials, chemotherapeutic agents, and oncolytic viruses, allowing precise delivery and active remodeling of the TME. These approaches collectively enhance tumor targeting, therapeutic efficacy, and spatial control within solid tumors. CONCLUSION: The integration of MSC biology with nanotechnology provides a powerful platform for regulating the TME and achieving precision oncology. While challenges related to safety, protumorigenic effects, and manufacturing scalability remain, recent advances are rapidly addressing these barriers. Engineered MSC-based therapies hold great promise to revolutionize cancer treatment and overcome the longstanding challenges of solid tumor therapy.

Chimeric antigen receptor natural killer (CAR-NK) cell therapy has emerged as a promising immunotherapeutic modality with potent cytotoxicity and a favorable safety profile. However, its therapeutic efficacy is often limited by poor infiltration into tumors and the profoundly immunosuppressive tumor microenvironment (TME). In hepatocellular carcinoma (HCC), one of the leading causes of cancer-related mortality, this suppressive TME severely compromises the function of CAR-NK cells. To overcome this limitation, we developed a combinatorial strategy integrating irreversible electroporation (IRE), a clinically approved nonthermal ablation modality capable of reshaping the TME, with glypican-3 (GPC3)-targeted CAR-NK cells generated via 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-functionalized lipid nanoparticle (LNP)-mediated gene delivery. IRE promoted immunogenic cell death and reprogrammed the TME through the release of damage-associated molecular patterns and chemokines, notably CX3CL1, thereby enhancing NK cell infiltration. Moreover, IRE-treated HCC cells exhibited heightened susceptibility to NK-mediated cytotoxicity through elevated intracellular reactive oxygen species, establishing a mechanism of immune sensitization. When combined with LNP-engineered GPC3-specific CAR-NK cells, this approach elicited synergistic antitumor activity, as demonstrated by superior tumor lysis in vitro and robust tumor regression in various HCC models without systemic toxicity. By coupling TME remodeling of IRE with the precision and safety of LNP-engineered CAR-NK cells, we propose a durable, clinically actionable treatment paradigm to overcome resistance in solid tumors, such as HCC.