With the rising global incidence of cancer and the limitations of traditional treatment methods, the integration of three-dimensional (3D) printing technology with drug delivery systems offers a promising solution for precision medicine. 3D printing, with its high flexibility and precise production control, allows for the accurate modulation of drug delivery systems, particularly in terms of targeted delivery and controlled drug release rates, thus significantly enhancing therapeutic efficacy and reducing side effects. This review focuses on the applications of various drug delivery forms, such as microneedle patches, implants, and tablets, in the treatment of cancers including breast cancer, melanoma, osteosarcoma, cervical cancer, colorectal cancer, and prostate cancer. Furthermore, the review explores the synergistic effects of combination therapies, such as photothermal therapy, chemotherapy, and immunotherapy, within 3D-printed drug delivery systems, and assesses their potential in addressing tumor recurrence, drug resistance, and treatment-related side effects. Despite the substantial promise of 3D printing technology in cancer treatment, challenges remain in material selection, process optimization, and production standardization. As technology continues to evolve and multidisciplinary collaborations deepen, 3D printing is expected to play an increasingly significant role in the future of precision medicine and personalized cancer therapy.

1. Introduction

According to statistics from the International Agency for Research on Cancer (IARC) 2022 statistics, the global number of new cancer cases is close to 20 million, with approximately 9.7 million deaths.¹ Currently, the main treatment options for cancer include surgery, radiotherapy, chemotherapy, immunotherapy, and hormone therapy. Despite the clinical use of various chemotherapy drugs with different mechanisms of action, the cure rate relying solely on chemotherapy remains at only 5%. Moreover, conventional chemotherapy drugs lack sufficient targeting ability and may accumulate in non-cancerous organs, causing severe toxicity to healthy tissues, such as hematopoietic cells in bone marrow and epithelial cells in the gastric mucosa.² Traditional delivery methods (such as oral formulations or intravenous injection) often suffer from poor drug solubility, leading to ineffective outcomes and significant side effects. Additionally, tumor heterogeneity further exacerbates the side effects and recurrence risks associated with treatment.³ This heterogeneity exists not only between different cancer types but also among individuals with the same cancer type, resulting in limited treatment efficacy, increased patient suffering, and restricted therapeutic outcomes.⁴ To address this issue, the design and optimization of drug delivery systems (DDS) are of paramount importance. An ideal DDS should ensure precise drug delivery to the tumor site, improving therapeutic outcomes while significantly reducing both local and systemic side effects, thereby enhancing the quality of life for cancer patients through intelligent and personalized treatments.⁵ This goal can potentially be achieved through the integration of three-dimensional (3D) printing technology and nanotechnology.⁶

Since the US Food and Drug Administration (FDA) approved the first 3D-printed tablet, Spritam® (levetiracetam), in 2015, 3D printing technology has gained significant attention in the medical field.⁷ With continuous advancements in 3D printing, researchers have explored new possibilities in medical applications such as drug delivery systems, tissue engineering, prosthetics manufacturing, and organ modeling, propelling it to become one of the fastest-growing technologies in the biomedical and pharmaceutical markets.⁸ The introduction of 3D printing technology has revolutionized traditional drug manufacturing and delivery methods. With its high design flexibility and on-demand production capabilities,

3D printing significantly reduces research and development costs and time, offering customized doses and personalized solutions for drug manufacturing.^9,10 This technology enables precise customization of drug doses, shapes, sizes, and release characteristics according to patient needs, particularly for drugs with narrow therapeutic windows that require drug monitoring, thus providing personalized treatment plans.^11,12 This revolutionary production method is transforming treatment from the traditional “one-size-fits-all” model to a more precise and individualized approach. Through innovative strategies, it fosters the development and improvement of novel drug delivery systems, presenting unprecedented opportunities and challenges for the evolution of drug delivery systems.^13,14

In this review, we begin by exploring various 3D printing technologies and their diverse applications in the development of drug delivery systems, particularly for anti-cancer treatment. We then discuss the innovations in the design and formulation of these delivery systems, focusing on their ability to target specific tumor sites, controlling drug release rates, and enhancing therapeutic outcomes. Finally, we provide a comprehensive overview of the challenges associated with material selection, process optimization, and clinical translation, while offering insights into the future potential of 3D printing in personalized cancer therapy (Figure 1).

2. 3D printing technology

The American Society for Testing and Materials (ASTM) classifies these technologies into seven categories based on the additive manufacturing processes involved.¹¹ This review primarily introduces and compares the 3D printing technologies widely used in the field of antitumor drug delivery, including fused deposition modeling (FDM), direct ink writing (DIW), binder jetting (BJ), stereolithography (SLA), digital light processing (DLP), and selective laser sintering (SLS) (Table 1).

Table 1. Comparison of different 3D printing technologies

Abbreviations: BJ, binder jetting; DIW, direct ink writing; DLP, digital light processing; FDM, fused deposition modeling; SLA, stereolithography; SLS, selective laser sintering.

2.1. Fused deposition modeling

FDM involves extruding thermoplastic materials in the form of filaments through a 3D printer’s extrusion nozzle at high temperatures. Together, the extruder and the build plate are maneuvered along the X, Y, and Z axes to build an object layer-by-layer.³⁸ There are dozens of accessible polymers that can be used in FDM printing, taking advantage of the intrinsic properties of thermoplastics which suit the quick transition from a solid state in the filament, to molten in the extruder, and rapidly reverting to solid after being deposited on the build plate.³⁹ Some of the most widely researched examples of these polymers include vinyl derivates such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), or cellulosic polymers like hydroxypropyl cellulose (HPMC) or ethyl cellulose (EC), but many others have also shown compatibility with FDM.^40,41 FDM printers in pharmaceutical applications almost exclusively create solid objects such as tablets, but have also shown success in producing buccal films and chewable, gummy-like objects.⁴² FDM allows for the easy fabrication of drug delivery systems with complex drug release profiles, catering to the specific release requirements of various dosage forms. Furthermore, printing parameters, such as dose, shape, and fill density percentage, are easily controllable and can be precisely adjusted to optimize drug performance.¹⁵ Due to its simplicity, flexibility, and cost-effectiveness, FDM is widely applied in drug delivery systems.⁴³

2.2. Direct ink writing

DIW can be categorized into droplet-based ink extrusion and continuous ink extrusion.²⁴ The material, in the form of viscoelastic ink, is extruded layer-by-layer through a nozzle, constructing scaffolds and other 3D geometries with desired properties and performance on a computer-controlled moving platform.⁴⁴ The curing of inks can be achieved through mechanisms such as solvent evaporation, temperature changes, gelation, or direct writing media, with the chosen curing mechanism also determining the ink’s rheological properties and solid content.⁴⁵ DIW offers material diversity, encompassing metals, ceramics, polymers, hydrogels, composites, and even biological cells.²¹ The ink exhibits shear-thinning behavior and significant viscoelasticity, enabling it to maintain stability after extrusion and facilitate interlayer deposition without collapse. Additionally, the ink contains a high solid content, which reduces volume and shape changes during subsequent processing.¹⁷ Furthermore, DIW employs room-temperature or low-temperature forming methods, alleviating the thermal stability concerns of active pharmaceutical ingredients (APIs).²² The mild drug formulation conditions of DIW present new processing opportunities for the anti-cancer drug delivery industry.

2.3. Binder jetting

BJ is a technology that utilizes a drop-on-demand (DoD) method, selectively spraying a liquid binder onto powder materials placed on the print bed.²⁷ This ink-jet printing process is primarily used to deposit inks made from low-viscosity solvent-based binders, with the material body typically presented as spherical powder particles on the print bed, thereby expanding the range of potential materials.²⁷ The advantages of BJ include its efficient and low-cost process, making it suitable for personalized drug delivery systems with customizable drug release characteristics. Moreover, this technology can operate at ambient temperatures that are suitable for heat-sensitive materials.⁴⁶ However, materials for binder jetting printing are limited to powders.⁴⁷ Powder characteristics significantly impact the printing process, and it is essential to fully understand these properties, including shape, appearance, size, distribution, fluidity, and bulk density of powder particles. When the liquid binder is applied to the powder bed, variations in powder morphology and particle size affect the binder’s penetration rate.⁴⁸ Typically, uneven powder distribution and excessive pore size can increase the penetration time.⁴⁹

2.4. Stereolithography

SLA utilizes a light-induced chain polymerization process to trigger a photopolymerization reaction, curing the photosensitive resin.³² Consequently, the oligomer-based liquid resin is photopolymerized to form a crosslinked and polymer-rich structure. SLA technology is mainly used for the preparation of hydrogels, where the nature of the produced matrix is highly dependent on the concentration and molecular weight of the polymer, which in turn influences the density of the gel formed. As a result of the high degree of crosslinking, SLA technology produces pore-less, dense, and compact matrices, that often yield slow-release profiles.⁵⁰ In terms of resolution, SLA can achieve high precision and resolution (1 μm), enabling the fabrication of components with complex internal structures and fine details.¹⁴ It also boasts a relatively high production speed.²⁹ SLA is capable of producing materials with enhanced compressive and tensile strength, shape-memory functionality, and improved hydrophilicity.^30,31 Due to its high precision and resolution, SLA is widely employed to develop various drug delivery systems with unique drug release rates.^51–54

2.5. Digital light processing

DLP uses a digital micromirror device to project ultraviolet (UV) light onto a photopolymer vat. By curing thin layers of photopolymer with predefined shapes and thicknesses, a 3D structure is assembled layer-by-layer.²⁷The main components of the DLP equipment include a projector, a digital micromirror device (DMD), and a vat of photopolymer resin or suspension. Light is generated by a projector at the bottom, which passes through the DMD. DMD consists of arranged cells of microscopic mirrors, each corresponding to one pixel in the image. Thus, the light is illuminated to precisely follow the shape of the layer on the vat window. For DLP, users slice the 3D computer-aided design structure to be printed into thin layers, and the set of layer images is inserted into the printer. Each layer image works as a grayscale mask to selectively cure the resin.⁵⁵ A photopolymer resin comprises photocurable or photosensitive oligomers and monomers in addition to a photoinitiator activated by a light with a specific wavelength and various chain extenders or crosslinking agents.⁵⁶ DLP utilizes photoreactive and photopolymerizable materials, allowing drugs to be directly loaded into the liquid prepolymer solution for printing.²⁷ DLP-based 3D printing offers superior printing speed compared to the point-by-point curing method of SLA-type printers, owing to its plane-by-plane printing technique.⁵⁷

2.6. Selective laser sintering

SLS involves depositing powder onto a powder bed layer, which is then heated to just below the sintering threshold temperature. A laser beam is directed onto the powder layer, triggering sintering, causing the powder particles to melt and bond with the previously consolidated layer.^58,59 Unlike other techniques, SLS does not require support structures because the powder itself supports the printed section. During operation, the manufacturing platform moves downward, depositing a fresh layer of powder, after which the laser scans and sinters the next layer of the object. This layer-by-layer process continues until the parts are fully formed, and they cool down inside the printer.⁶⁰ This technology enables the production of various materials such as plastics, metals, glass, ceramics, and composites. SLS for plastics and direct metal laser sintering (DMLS) or selective laser melting (SLM) for metals are the most common powder bed fusion systems employed at present. While these systems were once limited to high-value or custom parts, they have become more affordable and capable of producing a broader range of components.⁶¹ Due to their cost-effectiveness, high productivity, and material versatility, SLS 3D printers are extensively used in medical engineering for applications such as surgical models, medical device prototypes, and tissue engineering scaffolds.⁶²

3. Applications of 3D printing technology in fabricating various drug delivery systems

3D printing technology has revolutionized pharmaceutical development through its design flexibility and manufacturing precision. This advancement enables the precise fabrication of drug delivery systems with complex structures and tailored functions, significantly advancing personalized medicine. The review focuses on key applications including tablets, suppositories, microneedle, hydrogels, implants, nanocapsules, and microrobots (Table 2).

Table 2. Summary of 3D printing applications in fabricating drug dosage form

Abbreviations: BJ, binder jetting; DIW, direct ink writing; DLP, digital light processing; FDM, fused deposition modeling; MJ, material jetting; SLA, stereolithography; SSE, semi-solid extrusion.

3.1. Tablets

3D-printed tablets demonstrate superior advantages in manufacturing simplicity, dose uniformity, and personalized design, effectively overcoming the limitations of conventional tablets in structural adaptability and dimensional control.^63,70 Tablets can be designed for immediate release or sustained release kinetics, depending on therapeutic requirements. As the most widely accepted form of oral solid dosage, they have been extensively applied across various types and stages of cancer, including various gastrointestinal tumors, urinary system tumors, and others.^71,72 Thanawuth et al.⁷³ redesigned tablets with triangular/heptagonal compartments that exhibited extended release profiles (80% release in 24 h), contrasting with circular/square designs achieving complete release within 12 h. Mandati et al.’s comparative study⁷⁴ demonstrated that spherical tablets with 50% infill density accelerated drug release, where infill density exerted greater influence than shape variation. Zhao et al.⁷⁵ developed gastric-floating tablets via HME–FDM integration, establishing a positive correlation between release rate and surface area (1.5–4.5 mm radius).

3D printing can also produce tablets loaded with different drug forms, expanding formulation options. Zhang et al.¹⁶ fabricated core–shell tablets encapsulating solution/hydrogel/solid drugs, identifying prolonged release characteristics in liquid-phase formulations. Beck et al.’s HME-processed polymeric nano capsules enhanced drug processability,⁷⁶ while PAM-assisted self-nanoemulsifying systems significantly improve the solubility, stability, therapeutic efficacy, and bioavailability of active pharmaceutical ingredients (APIs).⁷⁷

3D printing enables the design of tablets with various geometric shapes to improve patient visual preferences and adherence to medication.⁷⁸ Januskaite et al.⁷⁹ used 3D printing to create chewable tablets with different flavors and colors, providing customized medication options for patients.

3.2. Suppositories

3D printing technology can transform nano drug delivery systems into suppository forms, demonstrating its potential in both localized and systemic drug delivery. This approach preserves nano-scale drug characteristics while achieving precision dosing and controlled release kinetics. Chatzitaki et al.⁸⁰ used pressure-assisted microinjection (PAM) with Gelucire 48 and Kolliphor RH 40 to improve drug release accuracy and bioavailability. Seoane-Viaño et al.⁶⁴ developed an infliximab-based bio-suppository with semi-solid extrusion (SSE), ensuring uniform distribution and controlled release, thereby addressing stability and uniformity challenges in rectal delivery. Awad et al.⁸¹ created an SSE-processed multi-drug suppository, incorporating budesonide and tofacitinib citrate to enhance treatment of rectal and colonic inflammation and enable personalized delivery of poorly soluble drugs. Suppositories are widely utilized in the local and systemic treatment of tumors such as cervical and colorectal cancers, due to their reduced gastrointestinal side effects, bypassing hepatic first-pass metabolism, ease of self-administration, and so on. These benefits contribute to their high biosafety and therapeutic efficacy.^82,83

3.3. Microneedles

Microneedles can break the stratum corneum barrier through minimally invasive methods, significantly enhancing transdermal drug delivery efficiency while avoiding nerve stimulation.⁸⁴ Compared to the limitations of traditional casting processes, such as limited structure and long production cycles, 3D printing technologies like SLA can create drug delivery systems with unique delivery characteristics, enabling microneedle structures with precision as fine as 10 μm and supporting multi-level porosity and complex geometric designs.^85–87 As a significant modality in transdermal drug delivery systems, microneedles facilitate the administration of various therapeutic agents to tumor sites through the skin. They are now widely used in the local treatment of tumors, such as melanoma, papilloma, glioma T-cell lymphoma, and breast cancer.^88,89 Uddin et al.⁹⁰ designed a cross-shaped microneedle array coated with anti-cancer drugs like cisplatin, which allowed for rapid drug release within 1 h and demonstrated significant anti-cancer activity. Joo et al.⁶⁷ proposed a novel self-locking microneedle system for precise skin insertion, attachment, and transdermal micro dose drug delivery, significantly improving the delivery of (αPD-L1 Ab)/SD-208 drugs in a melanoma mouse model. Lin et al.⁹¹ designed a multi-microchannel microneedle microoperation (4M) platform, using electroporation to facilitate drug transport across cell membranes and providing a concentrated and safe external electric field to accelerate deep drug penetration into cells. Wu et al.⁹² printed an acoustically activated, programmable microneedle patch, using digital control of acoustic signals to trigger drug pumping, demonstrating drug release characteristics tailored to user needs. This in situ acoustic drug delivery strategy offers advantages in miniaturization, operability, and intelligence, improving the controlled release capacity of microneedle patches.

3.4. Hydrogels

Hydrogels, as archetypal 3D network materials, have emerged as crucial carriers in antitumor drug delivery systems due to their exceptional water absorption capacity, mechanical flexibility, and self-healing properties.^65,66 Compared to conventional preparation methods that struggle to achieve precise structural and functional control, 3D printing technology enables accurate construction of hydrogel spatial topology, thereby endowing drug delivery systems with precise controlled release and intelligent responsive characteristics.^93,94In situ gelation, along with the formulation of various dosage forms using hydrogels, enables the delivery of multiple anti-cancer agents while simultaneously providing a robust platform for the repair of postoperative tissue defects. This strategy has been extensively applied in postoperative chemotherapy for cancers such as breast cancer, osteosarcoma, and malignant glioma, offering significant therapeutic benefits in terms of localized drug delivery and tissue regeneration.^95,96

Kuo et al.⁹⁷ developed a porous hybrid hydrogel based on gelatin and alginate (G/A) that can encapsulate and deliver bioactive compounds, such as enzymes and antioxidants. Phan et al.⁹⁸ created an injectable, biodegradable hydrogel based on cellulose nanocrystals (CNCs) incorporated into the amphiphilic copolymer PCLA, exhibiting excellent biocompatibility, controlled drug release, and multifunctional drug loading. Doxorubicin (DOX)-loaded hydrogel formulation significantly inhibited tumor growth. Hydrogels can also serve as materials for 3D printing other drug forms. Liu et al.⁹⁵ coated a uniform polycaprolactone (PCL) layer onto a 3D-printed alginate-gelatin hydrogel scaffold to create a core–shell fiber scaffold, further coated with polydopamine (PDA) to enhance photothermal properties. This enabled on-demand drug release triggered by near-infrared (NIR) laser, effectively inhibiting or eliminating tumors both in vitro and in vivo using drugs like DOX and photothermal therapy. Cheng et al.⁹⁹ used extrusion-based semi-solid 3D printing to fabricate theophylline hydrogel tablets with varying drug loads (75–125 mg), exhibiting high yield stress, storage modulus, and hardness.

3.5. Implants

The porous structure of 3D-printed implantable scaffolds improves drug loading efficiency and significantly enhances antitumor effects by targeting and extending drug release.¹⁰⁰ These scaffolds can also simultaneously load multiple anti-cancer drugs, enabling controlled sequential drug release. A wide range of metallic, polymeric, ceramic, and composite materials with diverse physicochemical properties can be processed through 3D printing to meet the clinical demands of scaffold fabrication.¹⁰¹ These implants play a crucial role in the treatment of tumors, such as breast cancer, bone tumors, cervical cancer, esophageal cancer, and lung cancer, as well as in the repair and support of postoperative tissue defects. Fang et al.⁶⁸ developed a sandwich-type composite material, by combining a 3D-printed scaffold loaded with combretastatin A4 (CA4) and electrospun fibers loaded with DOX, to form a multifunctional scaffold through time-controlled differential drug release. Wang et al.¹⁰² fabricated a coaxial 3D-printed scaffold that incorporated non-nucleoside STING agonist SR-717 and AKT inhibitor MK-2206 into the outer shell and core layers, respectively. The sequential and sustained release of these two drugs achieved synergistic STING activation, demonstrating significant antitumor effects. 3D-printed scaffolds can also provide a platform for immune modulation. Zhang et al.¹⁰³ developed a porous 3D-printed implantable scaffold with an ordered pore structure highly similar to real lymphatic structures, forming an artificial lymphatic network. This network facilitated the formation of antigen-specific immune cells, effectively eliminating tumor cells.

3.6. Nanocapsules

Nanocapsules are hollow spherical colloidal structures with sizes ranging from 10 to 1000 nm, where the core is encapsulated by a polymer shell, allowing for the simultaneous loading of both hydrophilic and hydrophobic drugs. Compared to other drug delivery systems, nanocapsules, as smart carriers, offer higher bioavailability, efficacy, and safety.¹⁰⁴ The introduction of 3D printing technology reduces the manufacturing time of nanocapsules and enhances automation, further expanding the applications of 3D-printed nanocapsule drug delivery systems.⁶ Nanocapsules using various carriers, including inorganic nanoparticles, dendrimers, and carbon nanotubes (CNTs), facilitating precise drug delivery and early cancer detection. They are widely applied in treating cancers such as breast cancer, osteosarcoma, prostate cancer, and colorectal cancer.¹⁰⁵ Rupp et al.¹⁰⁶ developed a small core–shell capsule composite material using a two-step 3D printing design. A dual-printing head system (FDM and liquid inkjet printing) was used to fabricate micro-sized core–shell capsules ranging from 100 to 800 μm, which can be used to encapsulate liquid drugs. By combining 3D printing technology with nanotechnology, nanocapsule suspensions containing various polymers (e.g., PCL, Eudragit® RL100) and different filling ratios were impregnated into 3D printing filaments, which can serve as a substrate for manufacturing other drug formulations.¹⁰⁷

3.7. Microrobots

Drug delivery is a key research area in the field of microrobots.¹⁰⁸ The integration of smart materials, magnetic control technology, and targeted therapy enables the active release of payloads, which is crucial for on-demand, precise, and efficient drug delivery.⁶⁹ With the advancement of 3D printing technology, further optimization of microrobot movement mechanisms and drug release control systems has broadened their potential applications in therapy, particularly in the targeted treatment of primary breast cancer, colorectal cancer, and other malignancies.^109,110 Bozuyuk et al.¹⁰⁹ designed a magnetically driven helical microswimmer using two-photon 3D printing technology, capable of precisely controlling the on-demand release of the chemotherapeutic drug DOX through external light stimulation. This system combines magnetic field-driven movement with light-triggered drug delivery, demonstrating excellent biocompatibility, biodegradability, and precise drug release regulation capabilities. Park et al.¹¹⁰ designed a magnetic-driven porous, biodegradable microrobot with a helical structure, which significantly improved drug release efficiency by optimizing the ultrasound pulse parameters and resolving cell damage issues. Ceylan et al.¹¹¹ developed a magnetically driven, enzyme-degradable double-helix microswimmer, which achieved drug delivery and release through rotational magnetic fields. The microswimmer, under the action of the MMP-2 enzyme, degraded within 118 h, rapidly releasing the embedded drugs or functional cargos.

4. 3D printing technology in anti-cancer drug delivery systems

4.1. Breast cancer

Breast cancer ranked as the second most commonly diagnosed cancer worldwide in 2022.¹ Although intensive-dose chemotherapy can enhance efficacy, particularly for triple-negative breast cancer (TNBC) patients, it inevitably increases drug side effects and compliance issues.¹¹² With the advancement of 3D printing technology, localized drug delivery systems, represented by implants, can reduce the administration time of chemotherapy, improve patient compliance, and enhance the controllability and sustainability of drug delivery¹¹³ (Table 3). Notably, implant-based reconstructions are increasingly utilized following mastectomy for breast reconstruction, preventing breast cancer recurrence, and controlling infections, further expanding their clinical applications.¹¹⁴ Yang et al.¹¹⁵ employed E-jet 3D printing technology to design poly-lactic-co-glycolic acid (PLGA) scaffolds that encapsulated chemotherapy drugs 5-fluorouracil and NVP-BEZ235, significantly reducing the drug dosage and prolonging the retention time of the drug concentration at the tumor site while minimizing exposure to normal tissues (Figure 2A). Hao et al.¹¹⁶ designed a drug carrier using polydimethylsiloxane (PDMS) for paclitaxel (PTX) and DOX microbead scaffolds, achieving sustained drug release for more than 3 weeks, effectively preventing tumor recurrence while reconstructing breast tissue. Su et al.¹¹⁷ developed a carbon quantum dot-curcumin (CCNPs) loading system with visual drug release capabilities (the fluorescence properties of CCNPs make drug release more convenient to be visualized and tracked, and it can be used for real-time drug release tracking in vivo), which also exhibited antimicrobial activity, promoted angiogenesis, and repaired tissue defects (Figure 2B). Zhang et al.¹¹⁸ designed a Pt-GelMA scaffold, 3D-printed using Pt (IV)-induced photopolymerization of methacrylate gelatin (GelMA) bioink, which effectively killed tumor cells and inhibited local tumor growth and distant metastasis post-surgery without any additional photosensitizers or chemotherapy drugs. The pH-sensitive drug delivery systems (gelatin–alginate composite scaffolds loaded with PTX and DOX) enable efficient targeted drug delivery and can regulate gene expression levels in breast cancer cells, such as CASP-3, Bax, and p53 (Figure 2C).^119,120 Time-programmed pulsed release implant that can control the release time based on the tumor’s internal microstructure has marked the first use in local dose-intensive chemotherapy for breast cancer¹²¹ (Figure 2D).

Table 3. Summary of 3D printing technology in anti-cancer drug delivery systems for breast cancer

Abbreviations: API, active pharmaceutical ingredient; BG, bioactive glass; CCNANA, CCNPs/sodium alginate/nanoclay/caffeic acid grafted chitosan; CCNPs, CDs-Cur nanoparticles; COX, cyclophosphamide; CTX, cefotaxime; DIW, direct ink writing; DOX, doxorubicin; GelMA, methacrylate gelatin; GT-AL, gelatin-alginate; MJ, material jetting; PDMS, polydimethylsiloxane; PLGA, poly-lactic-co-glycolic acid; PTX, paclitaxel; SLA, stereolithography.

Combination therapy is also an emerging field in breast cancer treatment. He et al.¹²² designed BG@NbSiR scaffolds that can eradicate primary tumors, activate immune responses, inhibit metastasis, prevent tumor recurrence (long-term immune memory), and accelerate osteogenesis through photothermal effect checkpoint blockade immunotherapy. Wei et al.¹²³ designed core–shell implants based on a hydrogel network, which undergoes a gel-to-sol transition under NIR light to release drugs on demand.

4.2. Melanoma

Melanoma is characterized by irregular patterns and uneven surfaces. It can spread to various organs such as the lungs, liver, bones, and brain through the respiratory tract and bloodstream.¹²⁴ Chemotherapeutic agents commonly used in clinical practice include immune checkpoint inhibitors for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4).¹²⁵ However, these drugs have only about 40% efficacy and face the challenge of drug resistance.¹²⁶ Given that melanoma is typically develops on the skin’s surface, 3D printing-based precision drug delivery systems, such as microneedles and dressings, offer a minimally invasive approach for targeted drug administration. These systems effectively suppress the growth and metastasis of primary melanoma while improving treatment outcomes and reducing systemic side effects^67,127 (Table 4).

Table 4. Summary of 3D printing technology in anti-cancer drug delivery systems for melanoma

Abbreviations: API, active pharmaceutical ingredient; CTLA-1, cytotoxic T-lymphocyte associated protein 1; DIW, direct ink writing; DLP, digital light processing; DOX, doxorubicin; GG: gellan gum; HME, hot-melt extrusion; ICG, indocyanine green; Nic, niclosamide; NiCu, nickel-copper; NPs, nanoparticles; PDA, polydopamine; PD-L1, programmed death-ligand 1; PLGR, PLA-graphene nanoplatelet; PVP, polyvinylpyrrolidone; SA, sodium alginate; SLA, stereolithography.

Microneedle patches are widely applied in melanoma treatment. Self-locking microneedles consist of a sharp skin-penetrating tip, a wide interlocking body, and a narrow base with mechanical supports, fabricated over a flexible hydrocolloid patch to enhance skin penetration accuracy on irregular surfaces. These patches carry transforming growth factor beta (TGF-β) inhibitor (SD-208) and anti-PD-L1 inhibitors, improving dose efficacy (Figure 3A).⁶⁷ Furthermore, magnesium particles react with interstitial fluid, generating rapid H₂ bubble formation to breach dermal barriers and enhance payload delivery. The combination of active release and delayed release provides stronger anti-cancer effects (Figure 3B).¹²⁸ Li et al.¹²⁹ designed high-resolution bilayer microneedles with an apex size of approximately 5 μm using pneumatic extrusion and controlled stretching. The patch designs can be tailored for cancers of varying severity, allowing personalized treatment with high therapeutic efficacy and minimal side effects (Figure 3C).

Dressings are also widely used for drug delivery in melanoma. Ćurić et al.¹³⁰ developed a customizable dressing combining nickel-copper nanoparticles (NiCu NPs) and polysaccharide hydrogels. NiCu NPs enhance the mechanical stability and anti-cancer activity of the dressing, which can be personalized according to patient needs. Kumar et al.¹³¹ developed a 3D-printed drug solution patch (3D-est-MediPatch) based on polylactic acid-graphene nanosheets (PLA-graphene), demonstrating good drug control release properties and therapeutic effects, while providing a portable platform for electrostimulation-assisted therapy. The heterogeneous hybrid hydrogel scaffold (SA-GG@PDA) composed of sodium alginate (SA), gellan gum (GG), and polydopamine nanoparticles (PDA NPs) carries the chemotherapy drug DOX, enabling sequential photothermal therapy combined with chemotherapy. This accelerates drug release while promoting angiogenesis and tissue repair (Figure 3D).¹³²

4.3. Osteosarcoma

Osteosarcoma is the most common primary malignant bone tumor, and the treatment of bone tumors remains one of the major challenges in cancer therapy.¹³³ Surgical resection often fails to completely remove tumor cells, leading to bone defects and poor prognosis.¹³⁴ Low-grade osteosarcoma, mainly parosteal osteosarcoma, is typically treated with surgical resection. High-grade osteosarcoma requires neoadjuvant chemotherapy with methotrexate, doxorubicin, and cisplatin (MAP), followed by surgery and continued postoperative chemotherapy.¹³⁵ With 3D printing technology, implantable drug delivery systems can effectively load drugs or functional materials due to their small size and controllable porosity, offering excellent bioactivity, biodegradability, and biocompatibility for repairing bone defects.^136–138

4.3.1. Chemotherapy

3D-printed scaffolds integrate antitumor, osteogenic, and antibacterial functions while modulating the immune microenvironment, offering a multifunctional approach to treating bone tumors (Table 5). Wang et al.¹³⁸ designed a spherical poly L-lactic acid (PLLA) implant loaded with multiple drugs, exhibiting excellent biodegradability and antitumor efficacy, with precise control over drug concentration and release rate. In mice, the scaffold released drugs for over 6 weeks (Figure 4A). Huang et al.¹³⁹ developed a Se/Sr/Zn-HA-PCL multifunctional composite scaffold, combining the antitumor effect of SeO₃²⁻ with the osteogenic and antibacterial properties of Sr²⁺ and Zn²⁺. Li et al.¹⁴⁰ successfully regulated the tumor immune microenvironment by incorporating colony-stimulating factor-1 receptor inhibitor (GW2580) onto a calcium phosphate scaffold, promoting M1 macrophage polarization to activate antitumor immunity (Figure 4B). Li et al.¹⁴¹ designed a time-sequential MgO₂/PLGA composite scaffold using low-temperature rapid prototyping (LT-RP) 3D printing technology could release H₂O₂ and Mg²⁺ in stages, achieving combined antitumor, antibacterial, and osteogenic effects. In the first 3 weeks, the scaffold released H₂O₂ for chemotherapeutic and immune microenvironment regulation, followed by 12 weeks of Mg²⁺ release to promote bone regeneration (Figure 4C). Phytochemicals show great potential in osteosarcoma treatment, but their poor solubility, bioavailability, and stability in free form can be improved by combining 3D-printed scaffolds with nanotechnology. Curcumin, apigenin, garlic extract, gingerol-Zn²⁺ metal complexes, and piperine, encapsulated in nanoparticles like liposomes, which are incorporated into 3D-printed calcium phosphate (CaP) scaffolds with specific porosity, exhibit controlled biphasic release in both acidic and physiological media (Figure 4D), significantly enhancing osteoblast proliferation, antibacterial activity, angiogenesis (e.g., mTOR upregulation), and antitumor effects.^142–146

Table 5. Summary of 3D printing technology in anti-cancer drug delivery systems for osteosarcoma (chemotherapy)

Abbreviations: API, active pharmaceutical ingredient; BJ, binder jetting; DIW, direct ink writing; DOX, doxorubicin; HBC, hydroxybutylchitosan; LT-RP, low-temperature rapid prototyping; OCS, oxidized chondroitin sulfate; PCL, polycaprolactone; PLLA, Poly L-lactic acid; SLA, stereolithography; TCP, tricalcium phosphate.

4.3.2. Photodynamic therapy and photothermal therapy

Photodynamic therapy (PDT) treats tumors by generating free radicals and singlet oxygen through laser irradiation, while photothermal therapy (PTT) uses NIR light for localized heating to kill cancer cells.^147,148 NIR laser-triggered drug or biomolecule release implants are commonly used smart drug delivery systems for tumor eradication and tissue regeneration (Table 6). 3D-printed scaffolds loaded with photothermal agents enhance NIR light penetration, promoting bone tissue regeneration.¹⁴⁹ Abie et al.¹⁵⁰ designed a 3D-printed scaffold made from silk fibroin, tannic acid, and PDA-modified SFO–TA–BGNF composite gel, exhibiting excellent photothermal antitumor and osteogenesis functions under NIR-I irradiation. Bifunctional scaffolds embedded with metal ions (Fe³⁺ and Mg²⁺) combine chemodynamic therapy (CDT) and PDA nanoparticles to achieve precise photothermal treatment under NIR-I laser, eradicating metastatic and residual tumor tissues.¹⁵¹ Additionally, Cap scaffolds integrated with a photosensitizer (Ce6) and an oxygen platform mediated by cyanobacteria improve antitumor effects of PDT, alleviate tumor hypoxia, and promote bone regeneration under NIR-I laser irradiation (Figure 4E).¹⁵²

Table 6. Summary of 3D printing technology in anti-cancer drug delivery systems for osteosarcoma (photodynamic therapy and photothermal therapy)

Abbreviations: API, active pharmaceutical ingredient; BGNF, bioactive glass nanofibers; CaP, CaCO3-polycaprolactone; CaPC, CeCyano-modified CaP scaffold; DIW, direct ink writing; FDM, fused deposition modeling; MJ, material jetting; NBGS, niobium carbide MXene-based bone-mimetic scaffold ; NIR, near-infrared; NPs, nanoparticles; NS, nanosheet; PCL, polycaprolactone; PDA, polydopamine; PLGA, poly-lactic-co-glycolic acid; SC, SrCuSi4O10; SFO, oxidized silk fibroin; TA, tannic acids; TCP, tricalcium phosphate.

Most studies use photothermal agents limited to NIR-I (650–950 nm), which have poor tissue penetration and are often non-bioactive, potentially causing systemic side effects after implantation.¹⁵³ Functionalization of 3D-printed PCL scaffolds with NIR-II photothermal agents (e.g., SC NSs, EB NSs, Nb2C MXene) enables photothermal therapy driven by NIR-II laser (1068 nm), significantly enhancing drug tissue penetration depth, efficiently eliminating OS, and promoting bone regeneration. This therapy also modulates gene expression related to cancer metabolism/progression and skeletal development^153–155 (Figure 4F).

4.3.3. Combination therapy

Postoperative residual cancer cells and chemotherapy resistance are key drawbacks of monotherapy in osteosarcoma treatment.¹⁵⁶ Combining chemotherapy with photothermal or magnetic hyperthermia therapies can achieve precise photothermal treatment and localized controlled release of chemotherapy drugs by adjusting the content of photothermal agents and anti-cancer drugs in 3D-printed scaffolds, significantly inhibiting osteosarcoma growth (Table 7).¹⁵⁶ PEEK/graphene composite scaffolds leverage the high photothermal conversion efficiency of graphene nanosheets and loaded antibiotics (STAC) or anti-cancer drugs (cisplatin, DDP) to achieve a multimodal therapy, including cancer cell ablation, bacterial clearance, and bone tissue repair.¹⁵⁷ Poly-d,l-lactic acid (PDLLA) polymers, as versatile mediums, enable photothermal and chemotherapy scaffolds to load various therapeutic agents, such as TiN particles and DOX on tricalcium phosphate (TCP) scaffolds or DOX and hemin on BGC scaffolds, creating multifunctional platforms with excellent photothermal responsiveness and high anti-cancer efficiency.^156,158 Using a metal-coordination self-assembly strategy, nanoscale two-dimensional copper-based conjugated metal-organic framework (cMOF)-engineered 3D-printed PCL scaffolds were developed for synergistic photothermal-chemodynamic therapy of osteosarcoma and accelerated bone regeneration (Figure 5A).¹⁵⁹ NIR-II photothermal tumor ablation combined with chemotherapy represents a major breakthrough in osteosarcoma treatment. Xu et al.¹⁶⁰ integrated FePSe₂ nanosheets with α-TCP scaffolds to achieve NIR-II photothermal tumor ablation and selenium ion release to promote angiogenesis and bone regeneration, while activating caspase-dependent apoptosis to prevent tumor recurrence (Figure 5B). Liang et al.¹⁶¹ designed BG@silicene scaffolds loaded with the epigenetic modulator IOX1, enhancing osteosarcoma sensitivity to photothermal therapy while reducing thermal damage to normal tissues. Multifunctional scaffolds can further combine catalytic therapies and oxygen release to improve treatment efficacy. For example, BG scaffolds combined with single-atom iron catalysts (FeSAC) enable nanocatalytic therapy through hydroxyl radical generation (Figure 5C).¹⁶² PCL/nHA/MgO₂/PDA composite scaffolds enhance tumor oxygenation and significantly improve photothermal therapy’s anti-cancer effect and bone repair capabilities (Figure 5D).¹⁶³

Table 7. Summary of 3D printing technology in anti-cancer drug delivery systems for osteosarcoma (combination therapy)

Abbreviations: API, active pharmaceutical ingredient; BGC, bioactive glass ceramics; DDP, drug cisplatin; DIW, direct ink writing; FDM, fused deposition modeling; FeSAC, single-atomic iron catalysts; DOX, doxorubicin; HHTP, hexahydroxytriphenylene; IOX1, 5-carboxy-8-hydroxyquinoline; nHA, nanohydroxyapatite; PCL, polycaprolactone; PDA, polydopamine; PEEK, polyetheretherketone; PDLLA, poly(d,l-lactide); STAC, stearyltrimethylammonium chloride; TCP, tricalcium phosphate.

Compared to PTT, magnetic hyperthermia therapy (MTT) offers unlimited tissue penetration and enhanced anti-cancer efficacy. MTT combined with CDT further promotes tumor ablation. Zhuang et al.¹⁶⁴ grew Fe₂S₃ layers on AKT scaffolds in situ to enhance reactive oxygen species (ROS) generation via magnetic hyperthermia, thereby strengthening chemodynamic therapy and achieving synergistic effects for eliminating residual tumor cells (Figure 5E). Wang et al.¹⁶⁵ designed a smart porous scaffold for on-demand drug release via magnetic field stimulation. The scaffold, fabricated using coaxial 3D printing, consists of hollow fiber alginate/iron oxide nanoparticle scaffolds, where the core encapsulates drugs, proteins, or live cells, releasing the loaded contents from the core under an applied magnetic field for magnetic-driven on-demand release (Figure 5F).

4.4. Cervical cancer

Cervical cancer is one of the most common malignancies in gynecology, with a secondary mortality rate only lower than that of breast cancer.¹⁶⁶ For locally advanced and mid-stage cervical cancer, treatment options include radical hysterectomy or definitive chemoradiotherapy.¹⁶⁷ However, these approaches are associated with high recurrence rates and postoperative tissue defects. Personalized 3D-printed cervical implants provide mechanical support and enable localized targeted chemotherapy delivery, reducing the risk of viral reinfection¹⁶⁸ (Table 8).

Table 8. Summary of 3D printing technology in anti-cancer drug delivery systems for cervical cancer

Abbreviations: API, active pharmaceutical ingredient; AuNP, gold nanoparticles; CDV, Cidofovir; DIW, direct ink writing; DSF, disulfiram; ERLPO, Eudragit RL powder; FDM, fused deposition modeling; HME, hot-melt extrusion; LDM, low-temperature deposition manufacturing; MJ, material jetting; PCL, polycaprolactone; PCX, paclitaxel; PEG, poly(ethylene glycol).

Using innovative low-temperature deposition manufacturing (LDM) 3D printing technology to load drug-loaded microspheres into polyurethane scaffolds, encapsulating JB protein solution could achieve precise loading and sustained release (over 1 month) of anti-HPV protein without compromising the protein’s viral inhibitory function and bioactivity (Figure 6A).^168,169 Kiseleva et al.¹⁷⁰ developed thermosensitive hydrogels based on Pluronic F127 and alginate, combined with gold nanoparticles (AuNP), releasing approximately 80% of the encapsulated AuNPs within 48 h, demonstrating unique nanoparticle release characteristics. Biologically adhesive vaginal films are suitable for personalized, precision treatment of cervical cancer. Almotairy et al.¹⁷¹ developed a sustained-release adhesive vaginal film based on thermoplastic extrusion technology using disulfiram (DSF), optimizing the formulation and printing parameters to achieve long-lasting release (24 h) and enhanced adhesion, effectively reducing drug dosage and improving patient compliance (Figure 6B). Varan et al.¹⁷² developed a biologically adhesive drug release film using inkjet printing technology, loading drugs like paclitaxel (PCX) and cidofovir (CDV), enhancing mechanical properties and achieving prolonged drug release (>12 h).