Engineered immune cell-based therapeutics for female reproductive tract cancers: Advances and future prospects

INTRODUCTION

The female reproductive tract is a multifaceted system that performs various complex processes associated with reproduction, such as producing gametes, regulating hormones, and providing support for fetal development. Each part of the system works in coordination with other and has its own importance; therefore, appropriate functioning of every organ is vital for women’s health.^[1] For instance, the vulva refers to the external female genitalia that comprises mons pubis, labia minora, labia majora, clitoris, and vaginal entrance.^[2] The mons pubis, a convex accumulation of adipose tissue situated above the pubic bone, becomes adorned with pubic hair during the onset of puberty. Similarly, the labia majora are the bigger, external skin folds that surround the vulva, while the labia minora, being thinner, are internal skin folds that protect the urethra and vaginal entrance. The clitoris, as an intricate organ abundant in sensory nerve endings, plays a crucial role in sexual stimulation and gratification.^[3] While, the vaginal entrance, situated anatomically between the urethra and anus, functions as the ingress to the vagina. The internal female reproductive organs comprise the ovaries, uterus, fallopian tubes, cervix, and vagina.^[4] Moreover, the ovaries are the primary female reproductive organs that generate ova and secrete hormones such as estrogen and progesterone. Adjacent to the uterus, the ovaries are situated bilaterally. Acting as a conduit between the ovaries and the uterus, the fallopian tubes facilitate the movement of the egg from the ovary to the uterus for fertilization.^[5] Furthermore, the uterus is the organ where a fertilized egg implants and develops into a fetus. Comprising three distinct layers, including the outside layer, middle muscle layer, and inner lining that undergoes thickening during the menstrual cycle, the structure is defined. The cervix represents the lower part of the uterus that connects to the vagina, facilitating the passage of sperm and menstrual fluid. In addition, the vagina is an anatomical structure that serves as a conduit connecting the external genitalia to the uterus and functions as the birth canal during childbirth and is also involved in sexual intercourse.^[6]

PHYSIOLOGY OF THE FEMALE REPRODUCTIVE SYSTEM

As it is known that the organs (both internal and external) of female reproductive tract works in excellent coordination to facilitate the processes of menstruation and procreation. The reproductive cycle of a woman can be broadly classified within the onset (menarche) and end (menopause) of the menstrual cycle. During menstrual cycle, the cyclical removal of ova occurs from the ovary for the probable fertilization by the male sperm. Normally, the menstrual cycle comprises three primary phases: The menses, proliferative, and secretory phase. The menses phase refers to the process of shedding the uterine lining and usually lasts for a period of 2–7 days. The proliferative phase refers to the period during which the endometrium, or uterine lining, undergoes thickening in anticipation of a potential pregnancy. This phase usually terminates in ovulation, which takes place on day 14 of a 28-day normal menstrual cycle.^[7] During the stage of secretory phase, the endometrium undergoes further thickening and organizes itself for a prospective conception. In the absence of fertilization, the menstrual cycle commences again with the onset of menstruation. Similarly, during the phase of ovulation, a mature follicle releases an egg (oocyte) into the fallopian tube. A spike in luteinizing hormone (LH) following the peak of estrogen levels starts this process.^[8] The menstrual cycle, ovulation, and maintenance of pregnancy are all dependent on hormones, primarily estrogen and progesterone, which control the female reproductive system. The coordinated action of hormones secreted by the pituitary gland, hypothalamus, and ovaries fine controls the working of the female reproductive system. Furthermore, they engage in collaboration through a feedback loop to control various phases of the reproductive cycle and prime the body for conception. Afterward, the hypothalamus releases a hormone known as gonadotropin-releasing hormone that invigorates the pituitary gland to release the follicle-stimulating hormone (FSH) and LH.^[4,9] When it comes to males, FSH works with Sertoli cells in the testes to help sperm production and encourage the growth of ovarian follicles in females. LH causes ovulation and encourages the corpus luteum to make progesterone in females. In males, it encourages the Leydig cells to make testosterone.^[10] Moreover, the ovaries serve as the main source of hormone synthesis in females, releasing estrogen and progesterone. In addition, estrogen, which the ovarian follicles produce primarily, stimulates the development of female secondary sexual traits and thickens the uterine lining throughout the menstrual cycle. After ovulation, the corpus luteum secretes progesterone to facilitate the initial phases of pregnancy and prepare the uterus for implantation.^[11] In addition, it hinders the secretion of FSH and LH. Furthermore, FSH and LH govern the menstrual cycle by managing the periodic fluctuations in estrogen and progesterone concentrations. During the follicular phase, FSH promotes the growth of follicles and the synthesis of estrogen, resulting in the thickening of the uterine lining.^[12] Following that, an increase in LH subsequently stimulates the liberation of the fully developed egg from the ovarian follicle, a process known as ovulation.^[13] In the luteal phase, the residual cells of the follicle gather to construct the corpus luteum, which produces progesterone to make the uterus ready for implantation.^[14] Failure of implantation leads to a decline in progesterone and estrogen levels, which, in turn, triggers menstruation.^[15]

FEMALE REPRODUCTIVE TRACT CANCERS (FRCs)

Reproductive cancers in females include malignant tumors that are formed in the female reproductive organs, including the ovaries, cervix, vagina, uterus, and vulva. Comprehending the unique attributes, factors that increase the likelihood of occurrence, and approaches for addressing each type of reproductive cancer is essential for successful prevention and control.^[16] The human papillomavirus (HPV) high-risk strains are primarily responsible for persistent infection in the cervix, the lowest portion of the uterus that attaches to the vagina, which is where cervical cancer originates.^[17] Cervical cancer in its initial stages is typically asymptomatic.^[18] However, when the illness advances, women may encounter irregular vaginal bleeding, pelvic pain, and heightened vaginal discharge. Regular screenings such as Pap smears and HPV tests are crucial for the early identification and prevention because cervical cancer can be substantially prevented with vaccination and regular screening procedures.^[19] Similarly, ovarian cancer, originating in the ovaries, is known for its vague signs such as abdominal distension, pelvic pain, and changes in urine habits, frequently leading to detection in a late stage. Various risk factors for the cancers of ovary include age, family history, and gene mutations, especially in the regions of BRCA1 and BRCA2 genes. Early detection of cancer poses challenges due to multiple causes; hence, treatment typically involves a combination of surgical intervention and chemotherapy.^[20] Conversely, uterine cancer, medically referred to as endometrial cancer, originates in the inner lining of the uterus. It is the predominant kind of cancer affecting the female reproductive system and is frequently detected in persons who have gone through menopause.^[21] Common symptoms encompass atypical vaginal bleeding, pelvic pain, and discomfort during sexual intercourse.^[22] The primary therapy for uterine cancer is surgical removal of the uterus, with a specific approach depending on the stage of the cancer. Furthermore, although less prevalent, vaginal and vulvar malignancies hold considerable importance in their regard. Unusual vaginal bleeding or discharge can be a sign of vaginal cancer, which develops from the walls of the vagina.^[23] On the other hand, vulvar cancer develops in the external genitalia and can be characterized by itching, pain, or visible lesions. These sorts are predominantly prevalent among elderly women. In addition, they could be associated with HPV infection. The standard course of treatment usually includes surgical intervention, and in certain instances, radiation therapy may also be employed. Aside from the more prevalent forms, there are also less common reproductive malignancies such as fallopian tube cancer and peritoneal cancer, which are frequently linked to the development of ovarian cancer.^[24] Every category of reproductive cancer possesses distinct risk factors and symptoms. This emphasizes the importance of being attentive and detecting a problem early to have successful therapy. Understanding these types of malignancies is crucial for improving outcomes and devising preventive measures for women’s health. Consequently, ongoing research and public health activities prioritize raising awareness, improving early detection tools, and reducing the impact of these diseases^[24] [Table 1].

CURRENT TREATMENT APPROACHES AND LIMITATIONS

The management of cancer has conventionally depended on three main modalities: Surgical intervention, chemotherapy, and radiation therapy. Surgery is commonly used to excise tumors and adjacent tissues, offering a possibly curative method for confined cancers.^[25] However, its efficacy decreases for late-stage malignancies or those that have spread to other parts of the body. Chemotherapy, a treatment method that employs cytotoxic chemicals to eliminate cancer cells that are dividing rapidly, continues to be a highly utilized alternative for treatment. However, it also leads to notable side effects as it affects normal, healthy cells.^[16,26] The drug’s impact on healthy cells results in notable side effects, including nausea, weariness, immunosuppression, skin irritation, and lethargy. Recent developments in cancer treatment have resulted in the creation of focused medicines.^[27] These treatments approaches have the objective of enhancing specificity and minimizing side effects. Targeted medicines specifically target molecular markers linked with cancer, therefore reducing harm to healthy cells.^[28] While targeted medicines have the potential to enhance outcomes, they may also give rise to enduring side effects that are now being studied. Interestingly, immunotherapy, a therapeutic method that uses body’s own immune system to remove cancer cells, has shown significant potential in the management of many types of cancer. Although immunotherapy can result in long-lasting responses in certain people, not all individuals exhibit a response to this treatment. Moreover, it can lead to immune-related harmful consequences.^[29] However, traditional cancer treatments encounter many restrictions despite these progressions. An important obstacle is the variability of malignancies, which results in diverse therapeutic responses.^[30] Moreover, the development of resistance to chemotherapy and targeted therapies is a significant challenge, typically necessitating the utilization of numerous treatments to enhance efficacy. Furthermore, considerations such as financial implications, the limited supply, and the requirement for specialist healthcare facilities can impede the accessibility of novel therapies.^[20,31] In addition, researchers are currently investigating novel treatments such as stem cell therapy, gene therapy, and natural antioxidants to address the limitations of conventional therapies. Furthermore, stem cell therapy has shown promise in enhancing the process of recuperation. In addition, it demonstrates the potential to diminish the sizes of tumors.^[32] However, there are ongoing worries regarding its long-term durability and its potential to cause the development of tumors. Gene therapy aims to rectify genetic abnormalities and bolster the body’s ability to fight against tumors.^[33] Nevertheless, it is imperative to tackle the obstacles associated with delivery systems and immunological responses. However, despite the ready availability of natural antioxidants, they often face challenges concerning their absorption and potential toxicity.^[34]

IMMUNE CELL ENGINEERING: AN ALTERNATE THERAPEUTIC OPTION

The management of cancer has traditionally relied on several primary modalities, each with its own advantages and limitations. Understanding these options is crucial for evaluating the emerging field of immune cell engineering as an alternative therapeutic strategy. The treatment of cancer often encompasses various modalities, each possessing distinct mechanisms, benefits, and drawbacks [Figure 1]. Surgery frequently serves as the primary treatment for localized tumors, offering the possibility of total excision; nevertheless, its efficacy markedly declines in advanced stages characterized by metastasis. Chemotherapy, a fundamental component of cancer therapy, utilizes cytotoxic chemicals to target rapidly proliferating cells, effectively addressing various malignancies while also causing significant side effects due to harm to normal, healthy cells.^[16] Radiation therapy employs high-energy radiation to eradicate cancer cells and is predominantly successful for confined tumors, while it may also damage surrounding healthy tissues. Targeted therapy seeks to engage specific molecular targets linked to cancer, thereby reducing damage to normal cells; however, the absence of appropriate targets may limit its efficacy.^[26] Immunotherapy utilizes the body’s immune system to combat cancer and has demonstrated potential in specific instances; however, not all patients exhibit positive responses, and immune-related side effects may arise. Stem cell therapy aims to restore damaged tissues and shows promise in addressing hematological malignancies; yet, apprehensions regarding long-term effects and the possibility for tumorigenesis persist. Gene therapy seeks to rectify genetic anomalies linked to cancer, offering potential for improved immune responses against tumors; yet, obstacles concerning delivery mechanisms and immunological reactions remain. Natural antioxidants seek to mitigate oxidative stress in the body and may provide a less hazardous alternative to traditional medicines; nevertheless, challenges related to absorption and efficacy may restrict their application. Each of these methodologies offers distinct advantages and obstacles that guide the investigation of novel tactics such as immune cell engineering as a potential therapeutic alternative.^[27] With an understanding of these traditional approaches and their respective pros and cons, we can now explore immune cell engineering as a promising alternative therapeutic option that seeks to overcome many limitations faced by conventional treatments.

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Figure 1:

Image showing different approaches currently used for the treatment of cancer.

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The field of cancer immunotherapy has seen substantial transformation with the advancement of immune cell engineering, a technique that harnesses the capabilities of the immune system to detect and eliminate cancer cells. In addition, this novel technique has garnered significant attention due to its capacity to mitigate the limitations of conventional cancer treatments such as chemotherapy and radiation therapy.^[35] Furthermore, a key benefit of immune cell engineering is its capacity to selectively target tumor antigens, while limiting any unintended impact on healthy organs. In addition, cancer cells have evolved sophisticated mechanisms to evade or diminish the effectiveness of the immune system, such as downregulating tumor markers or secreting immunosuppressive chemicals.^[36] To counteract these, it is proposed to create modified immune cells that can specifically target various antigens, produce cytokines that combat tumors, or interfere with inhibitory pathways. Consequently, this enhances the immune system’s ability to locate and target cancer cells.^[37] Furthermore, genetic engineering enables the exact alteration of immune cells to enhance their ability to target tumors and their potential to destroy them through developing chimeric receptors. One such type of cell is chimeric antigen receptor (CAR) T-cells, which are engineered to possess receptors that recognize the antigens specific for tumor cells.^[38] Consequently, this enhances their ability to eliminate cancer cells while minimizing the harm to normal cells. This technique has demonstrated exceptional efficacy in the management of hematological malignancies, including acute lymphoblastic leukemia and diffuse large B-cell lymphoma.^[30,39] On the other hand, solid tumors provide extra difficulties due to the immunosuppressive environment around the tumor and the absence of appropriate targets, despite the encouraging outcomes observed in blood malignancies.^[40] Continue research is underway to find ways that overcome these obstacles and improve the utilization of modified immune cells for the treatment of solid tumors.^[41] These endeavors entail modifying immune cells to withstand signals that inhibit the immune system within the tumor microenvironment and identifying novel tumor-specific antigens for precise targeting.^[42] Moreover, immune cell engineering can facilitate the development of pre-made treatments in which cells obtained from healthy donors are altered and prepared for quick utilization.^[43] In addition, this method can enhance the availability of these treatments to a wider range of patients, as therapies utilizing the patient’s genetically modified T-cells can be laborious and expensive to produce.^[43] It is also possible to create modified immune cells that have safety mechanisms, enabling their controlled removal in the event of serious adverse reactions. Modifications can also augment the longevity and expansion of transplanted cells, resulting in more enduring anti-tumor reactions^[44] [Figure 2].

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Figure 2:

Image illustrating a brief overview of various stages involved in immune cell engineering, beginning with the collection of blood cells and progressing through the activation of immune cells. This process is crucial for developing effective therapies that enhance the body’s ability to combat diseases like cancer. CAR-NK: Chimeric antigen receptor-Natural Killer cells, CAR-M: Chimeric antigen receptor-Macrophages, CAR-T: Chimeric antigen receptor-T cells, TCR-T: T cell receptor-T cells, DC: Dendritic cells.

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IMMUNE CELL ENGINEERING IN FEMALE REPRODUCTIVE CANCERS

Immune cells have the potential to recognize and attack cancer cells, thereby improving therapeutic outcomes. Utilizing immune cells can transform the treatment of these cancers, often have limited treatment options and poor prognosis.^[67] Developing engineered immune cells is one such significant advancement in this field that can better identify and eliminate cancer cells of female reproductive tract. Dr. Coukos’ research at the University of Pennsylvania focuses on developing molecules that increase the ability of immune cell receptors to attach to tumor cells.^[68] By engineering these receptors to attach more strongly to ovarian cancer cells, the modified immune cells demonstrate a greater capacity to kill these malignant cells effectively. Early studies in mouse models have shown promising results, indicating that these engineered immune cells could have strong anti-cancer effects in women with advanced ovarian cancer. In addition to ovarian cancer, immune cell engineering is also being explored for other reproductive cancers.^[69] As an example, CAR T-cell therapy has been adapted to target specific antigens linked to gynecological tumors. CAR T-cell therapy primarily aims to modify patient’s T-cells to express specific receptors, which can potentially recognize and eradicate cancer cells. The approach has been observed to show potential success in treating hematological malignancies and is now being investigated for solid tumors, including those in the female reproductive system. A study has developed an innovative CAR T-cell therapy targeting the folate receptor alpha, which is overexpressed in ovarian, endometrial, and cervical cancers. Early clinical trials have demonstrated promising results, with some patients experiencing complete remission of their cancer. Furthermore, safety concerns with engineered immune cells have led to the development of advanced systems for better therapy control.^[70] A study reports a safety mechanism for CAR T-cells called versatile protease regulatable (VIPER) CAR - T cells, which can be activated or deactivated using an Food and Drug Administration (FDA)-approved antiviral medication. This development aims to reduce the likelihood of severe side effects, like cytokine release syndrome, which may result from the overactivation of engineered T-cells. Furthermore, researchers are investigating the use of ready-made engineered immune cells from healthy donors, which could improve the affordability and availability of these treatments.^[71] Despite the potential of immune cell engineering, challenges remain in effectively applying these therapies to solid tumors, including those found in the female reproductive tract. The tumor microenvironment in solid tumors can be immunosuppressive, which makes it challenging for engineered immune cells to function optimally. Ongoing research is focused on overcoming these barriers by improving the persistence and efficacy of engineered immune cells in such environments. Strategies include combining immune cell engineering with other therapies, such as checkpoint inhibitors or targeted drugs, to create a more favorable tumor microenvironment for the engineered cells to thrive in.

Immune cell engineering have emerged as a transformative approach in the treatment of women’s reproductive cancers, including ovarian, cervical, and uterine cancers.^[72] This innovative strategy involves modifying immune cells to enhance their ability to recognize and eliminate cancer cells, ultimately improving therapeutic outcomes.^[73] Due to advancements in technology and a better understanding of tumor biology, the applications of immune cell engineering in women’s reproductive cancers are numerous and constantly changing.^[74] One of the most promising applications of engineered immune cells is in the treatment of ovarian cancer.^[75] By creating molecules that bind more tightly to tumor cells, these engineered immune cells demonstrate enhanced cytotoxicity compared to their unmodified counterparts.^[76] Early studies in mouse models have shown that these engineered receptors can lead to potent anti-tumor effects, paving the way for potential clinical applications in women with advanced ovarian cancer.^[77]

IMPACT OF IMMUNE CELL ENGINEERING ON FERTILITY AND PREGNANCY

The engineering of immune cells have emerged as a transformative approach in the field of reproductive health, with the potential to significantly impact fertility and pregnancy outcomes. Immune cells, including T-cells, NK cells, and DCs, play crucial roles in maintaining reproductive homeostasis, facilitating embryo implantation, and supporting successful pregnancies.^[98] However, the manipulation of these immune cells through engineering techniques can have both beneficial and detrimental effects on fertility and pregnancy, necessitating a thorough understanding of their functions and interactions within the reproductive system. Immune cells are integral to various stages of reproduction, including ovarian follicle development, ovulation, and embryo implantation.^[99] For instance, uterine NK cells contribute to the remodeling of maternal blood vessels and the establishment of a supportive environment for the implanting embryo. In addition, macrophages and T-cells are involved in regulating the immune tolerance necessary to prevent maternal rejection of the semi-allergenic fetus. The dynamic interactions between these immune cells and reproductive tissues are essential for successful conception and pregnancy maintenance.^[100] Research has highlighted the importance of maintaining a delicate balance of immune responses throughout the reproductive cycle, as both excessive inflammation and immune suppression can lead to adverse outcomes.^[101] Immune cell engineering, particularly through techniques such as CAR T-cell therapy, has shown promise in enhancing immune responses against tumors.^[102] However, the application of these technologies in reproductive health raises important considerations. For example, while engineered T-cells can be designed to target specific cancer cells, their activation can inadvertently disrupt the delicate balance of immune tolerance required during pregnancy.^[103] This disruption may lead to complications such as miscarriage or preterm labor. Conversely, the strategic engineering of immune cells could be harnessed to improve fertility outcomes. Increasing the number of Treg cells in the uterine microenvironment has been shown to improve the chances of getting pregnant. This is especially true for women who lose multiple pregnancies or cannot get pregnant due to immune system issues.

LIMITATIONS AND HURDLES

Despite the potential benefits of immune cell engineering in reproductive health, several documented challenges must be addressed:

NANOMATERIALS-BASED STRATEGIES FOR IMMUNE CELL ENGINEERING

Nanomaterial’s-based strategies have emerged as innovative solutions in cancer treatment, leveraging the inimitable properties of nanomaterials to enhance therapeutic efficacy, improve drug delivery, and overcome the limitations of conventional therapies.^[109] These strategies encompass a varied range of applications, including targeted drug delivery, photothermal therapy (PTT), and gene therapy, and are particularly valuable in addressing the challenges posed by tumor cells such as drug resistance and heterogeneity.^[110] Nanomaterials can be engineered to interact with biological systems at the cellular and molecular levels. This allows for the development of nanocarriers that can encapsulate therapeutic agents, such as chemotherapeutics, ribonucleic acid (RNA), or proteins, and deliver them precisely to tumor sites.^[111] Nanoparticles can be made to react to certain things, such as changes in pH or the presence of enzymes. This makes it easier to release drugs slowly at the tumor site while minimizing their effects on the rest of the body. Recent advancements have highlighted the use of multifunctional nanosystems that integrate various therapeutic modalities, including photothermal and photodynamic therapies, to enhance the destruction of cancer cells and improve treatment outcomes^[112] [Figure 3].

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Figure 3:

Image showing the different strategies employed nanoparticles in targeting mechanisms for cancer immunotherapy treatment. This image highlights innovative approaches that increase therapeutic efficacy and specificity, creating the way for more effective cancer treatments.

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Nanoparticles can be engineered to target specific tumor markers, allowing for selective delivery of therapeutic agents. This targeted approach reduces off-target effects and enhances the therapeutic index of drugs. For example, gold nanoparticles have been utilized for their ability to enhance the efficacy of radiotherapy through localized heating when exposed to light.^[113] Nanomaterials are also being explored as non-viral vectors for gene delivery. They can encapsulate genetic materials such as plasmid deoxyribonucleic acid (DNA), messenger RNA (mRNA), or small interfering RNA (siRNA), facilitating their transport into target cells. This approach is particularly promising for treating genetic disorders and cancers by delivering therapeutic genes that can induce apoptosis in cancer cells or correct genetic defects. Nanomaterials can be employed in PTT and photodynamic therapy (PDT) to selectively destroy cancer cells. In PTT, the involved nanoparticles potentially absorb light and convert it into heat, leading to localized hyperthermia that can kill cancer cells. In PDT, light activates photosensitizers to produce reactive oxygen species, which cause cell death. These techniques can be enhanced using nanomaterials that improve light penetration and retention in tumors, thereby increasing treatment efficacy.^[114] Nanomaterials have become integral to the advancement of immune cell engineering, providing innovative approaches to enhance immune responses and improve therapeutic efficacy in various diseases, including cancer. Nanomaterials are useful in immunotherapy because their size, surface area, and ability to be functionalized make it possible to deliver therapeutic agents precisely and control how long they stay in the body. One of the primary applications of nanomaterials in immune cell engineering is the targeted delivery of therapeutic agents to specific immune cells. To selectively target immune cells, we can change the surface properties of nanoparticles and add ligands that bind to specific receptors on those cells.^[115] This approach enhances the accumulation of drugs or genetic materials in the desired immune cell populations, thereby increasing therapeutic efficacy while minimizing systemic side effects. For instance, nanoparticles have been designed to deliver immune checkpoint inhibitors directly to T-cells, improving their activation and proliferation in the tumor microenvironment, which is crucial for effective cancer immunotherapy. Nanomaterials also play a significant role in the development of nano-vaccines, which enhance the immunogenicity of antigens. By encapsulating antigens within nanoparticles, these vaccines can protect against degradation and improve stability, ensuring effective delivery to immune cells.^[116] In addition, nano-vaccines can co-deliver adjuvants, which further stimulate immune responses. Recent studies have demonstrated that nano-vaccines can effectively activate immune systems, leading to improved protection against tumors and infectious diseases. Nanomaterials can also be engineered to modulate the activity of specific immune cell types. For example, nanoparticles can be designed to activate DCs, enhancing their ability to present antigens and stimulate T-cell responses. This is particularly important in cancer therapy, where effective antigen presentation is crucial for generating robust anti-tumor immunity. In addition, engineered nanoparticles can be used to polarize macrophages toward a pro-inflammatory or anti-inflammatory phenotype, depending on the therapeutic needs, thereby influencing the overall immune response. The ability of nanomaterials to facilitate gene delivery is another critical aspect of their role in immune cell engineering. Nanoparticles can hold different kinds of genetic material, such as plasmid DNA, mRNA, or siRNA.^[117] This makes it possible to change immune cells so that they make certain antigens or cytokines. This capability is particularly promising for enhancing the therapeutic potential of immune cells. For example, nanoparticles have been used to send mRNA that encodes tumor antigens to DCs. This causes strong T-cell responses against the tumor. The integration of nanomaterials with other therapeutic modalities, such as immunotherapy and chemotherapy, represents a promising direction in immune cell engineering. By combining nanomaterials with immune checkpoint inhibitors or CAR T-cell therapies, various studies aim to create synergistic effects that enhance overall treatment outcomes. For example, nanoparticles can be used to deliver small-molecule immunomodulators to T-cells, improving their function and persistence in the tumor microenvironment.^[118] Moreover, nanoparticles have emerged as promising carriers for the delivery of immune modulators, offering several advantages over conventional delivery methods.^[119] By encapsulating or conjugating immune stimulating agents within nanoparticles, the stability, specificity and efficacy of these modulators can be increased with minimal off target effects and targets.^[120] This approach has significant implications for the development of more effective vaccines, immunotherapies, and treatments for immune-related disorders. Nanoparticles can protect immune modulators from degradation and clearance, thereby improving their stability and bioavailability.^[121] For example, encapsulating cytokines or adjuvants within nanoparticles can shield them from enzymatic degradation and prolong their circulation time in the body. This enhanced stability can lead to more sustained release and prolonged immunomodulatory effects. It can be engineered to target specific immune cell populations, such as DCs, T-cells, or B-cells, by incorporating ligands or antibodies on their surface.^[122] This targeted delivery can help immune modulators get into the right cell types more easily, which can make it easier to activate or suppress immune responses. When used in combination with antigens, nanoparticle-delivered immune modulators can enhance the immunogenicity of vaccines. By co-delivering antigens and adjuvants within the same nanoparticle, scientists can create a synergistic effect that promotes antigen presentation, co-stimulation, and the generation of robust, long-lasting immune responses.^[123] It can be made to change the way certain types of immune cells work.^[124] For example, they can be used to treat autoimmune diseases by encouraging the differentiation of Tregs cells or to treat cancer by making NK cells more effective at killing cancer cells.^[125] By delivering cytokines, small molecules, or genetic materials that target key signaling pathways, nanoparticles can fine-tune the activity of immune cells.^[126] In the context of cancer immunotherapy, nanoparticles can be used to overcome the immunosuppressive tumor microenvironment. Nanoparticles can strengthen immune systems against tumors by delivering toll-like receptor agonists, immune checkpoint inhibitors, or other immunostimulatory agents.^[127] Nanotechnology plays a pivotal role in enhancing immune cell engineering strategies. The nanoparticles deliver immune modulators or antigens directly to immune cells and enhances the activation and proliferation of these cells. Nanoparticles can also enhance the stability and bioavailability of therapeutic agents, allowing for more effective immunotherapy. The integration of nanotechnology with immune cell engineering holds promises for creating more effective and targeted treatments for gynecological cancers. The future of immune cell engineering in women’s reproductive cancers is promising, with ongoing research aimed at optimizing the design and application of engineered immune cells.^[128] Advances in understanding tumor microenvironments and immune evasion mechanisms will inform the development of more effective therapies. Furthermore, looking into combination therapies that use immune cell engineering along with other types of treatment, such as radiation and chemotherapy, may have positive effects that help patients do better. Furthermore, personalized medicine approaches, which tailor treatments based on individual tumor characteristics and immune profiles, are likely to play a significant role in the future of immune cell engineering. By leveraging the unique aspects of each patient’s cancer, researchers can develop targeted therapies that maximize efficacy while minimizing adverse effects.^[129]

CONCLUSION AND FUTURE PERSPECTIVES

The field of immune cell engineering has recently garnered significant attention as a pioneering approach to combating women’s reproductive cancers. This innovative strategy bolsters the immune system’s capacity to identify and eradicate malignancies, such as ovarian, cervical, and uterine cancers. Engineered immune cells have exhibited promising potential in preclinical and early clinical investigations, encompassing diverse modalities such as CAR T-cell therapy, DC vaccines, and nanoparticle-based delivery systems. These studies have shown significant promise for patients who have limited treatment options. The advancement of this field relies on incorporating cutting-edge technologies and gaining a deep understanding of tumor biology. This is expected to drive the development of more effective and personalized therapies. Exploring combined approaches that involve modifying immune cells and using established treatments such as immunotherapy and chemotherapy shows great potential in overcoming the challenges presented by different types of tumors and immune evasion strategies. In addition, it is essential to implement safety measures in engineered immune cells to ensure patient well-being and minimize side effects. This will facilitate the wider adoption of these therapies in clinical settings. The incorporation of nanotechnology into immune cell engineering further expands the horizons for precise and efficient delivery of therapeutic agents, thereby paving the way for a new era of innovative treatment modalities. In summary, the prospects for immune cell engineering in women’s reproductive cancers are highly optimistic, with the potential to revolutionize the landscape of cancer treatment. To fully realize the potential of these advanced therapeutic strategies, sustained research endeavors and interdisciplinary collaboration among immunologists, oncologists, and engineers will be paramount. As we progress, the steadfast commitment to leveraging the power of the immune system through engineering will play a pivotal role in achieving more effective, personalized, and safer cancer therapies.

CONCLUSION

The engineered immune cell based approaches seems to be promising and further research and trials will certainly provide future treatment options for female reproductive tract cancers.