Cancer is one of the principal causes of death all over the world. Generally, cancer occurrence and death rates are speedily rising worldwide; this demonstrates both aging and an increase in the population, along with alterations in the occurrence and spreading of the main risk factors for cancer, which are mostly associated with socioeconomic growth. In 2020, approximately 19.3 million new cancer cases and almost 10.0 million cancer expiries occurred worldwide [1].

Besides surgery, present cancer treatments deeply depend on radiation and chemotherapeutic agents, which also affect “normal” cells and result in toxicity in other organs of the patient’s body. As a result, there is an increasing interest in developing extremely effective therapeutic agents that are able to conquer biological obstacles, differentiate between malignant and normal cells, specifically aim at cancerous parts, and give an “intelligent” response to the cancerous tissue for releasing therapeutic agents in the proper place [2]. The cancerous environment, often referred to as the tumor microenvironment, consists of diverse cellular and non-cellular components with specific properties that make it different from the normal physiological conditions present in normal tissues. These special properties have been widely investigated in past years and can be used for different delivery strategies.

Nanoparticles have been the most significant delivery systems of the past few decades in pharmaceutical sciences due to their special characteristics, such as large surface area, high encapsulation efficiency, and controllable release properties. Modifying nanoparticles’ features to have the most efficient system has always been a challenge for formulation scientists and an ever-growing field of study.

Targeted nanoparticles for cancer treatment have been the subject of many studies in the past decade. Targeted cancer therapy can differentiate the minor alterations between normal and malignant conditions. These kinds of therapies exhibit more effectiveness and fewer undesirable adverse effects than conventional treatments. Conventional and non-specific therapies usually have unwanted properties, such as quick removal of the drug and administration of high doses of the drug, which are usually not economical and highly toxic. Nanoparticles have overcome many obstacles of conventional chemotherapeutics, such as not fully efficient biodistribution, side effects, and further drug resistance [3].

New generations of nanoparticles can be modified in almost every aspect for more efficient delivery of therapeutics. Nanoparticles can encapsulate diverse types of therapeutics, such as small molecule drugs, therapeutic antibodies, genetic material, and imaging agents. They can be chemically designed to be responsive to specific properties of cancerous tissue, such as hypoxia and acidic pH. Additionally, nanoparticles can be modified on their surface by targeting antibodies, aptamers, or other types of cellular ligands for cargo delivery to the desired cells.

It is absolutely necessary for researchers working in the field of cancer therapy to obtain fundamental knowledge about the properties of the tumor microenvironment that can be used for designing novel nanoparticle-based delivery systems that would lead to more efficient methods with improved clinical results. There are several different strategies for targeted cancer therapy, from methods targeting the features of the tumor microenvironment to methods targeting the cellular and molecular receptors present in malignant tissues.

2. Tumor Microenvironment, a Limitation Turned into an Advantage

Conventional cancer chemotherapeutics usually kill cancer cells directly, and their efficacy is dependent on their access and penetration to cancer cells [4]. However, tumor cells are not the only responsible factors for cancer progression, noncancerous stromal cells are also present and highly interactive in the tumor environment [5]. Stromal cells form the tumor microenvironment (TME), which provides support for the proliferation of cancer cells, assisting the escape from natural and immunological mechanisms for programmed cell death. As reported by Hanahan et al. [6], six hallmarks contribute to the progress of cancer and the formation of the TME by cell signaling. These hallmarks are evading cell death pathways, bypassing growth suppressors, constant proliferation signaling, formation of neovasculature (angiogenesis), initiation of metastasis, and proliferative immortality. The tumor microenvironment consists of cellular and non-cellular components. The former includes numerous stromal cells, such as cancer-associated fibroblasts (CAFs), endothelial cells (ECs), tumor-infiltrating lymphocytes (TILs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). The latter consists of non-soluble elements, such as the extracellular matrix (ECM), and soluble parts, such as growth factors, several cytokines and chemokines, and metabolites ^{[7][8][9][10]}[7,8,9,10]. Two main properties of the TME are hypoxia and acidic pH because of cellular metabolism and nutritional requirements. Cancer cells need a high amount of oxygen to proliferate and grow, and since even angiogenesis cannot provide the excess oxygen for the cancerous tissue, the TME is always in a hypoxic condition. Cancer cells boost glycolysis and other metabolic pathways to stand the insufficient oxygen amounts. Another important property, especially in solid tumors, is the impermeability and difficult penetration of the nanomedicine, which requires further modification in the physical and chemical properties of the nanoparticles to increase their permeability inside the TME ^[11][12][13][11,12,13]. The TME is fundamentally immunosuppressive to defend tumor cells against immune surveillance. It is also a dynamic environment for supporting quick tumor growth and standing all stress factors, for instance, chemotherapy ^[14][15][14,15]. There is an overexpression of growth factors either on cancer cells or other present cells in the TME to provide the increasing needs of cancer cells. Defections in tumor protein 53 (TP53) and retinoblastoma (RB)-associated pathways (which are responsible for detecting any irregularities and starting the procedure of apoptosis) lead these cells to bypass the apoptotic process. Angiogenesis, another important factor for cancer progression, is essential for the cancerous tissue to provide oxygen for cells and is stimulated by several growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Due to extreme growth levels and an excessive amount of division sets, two obstacles for replication arise: the cell senescence and crisis, in which the cell moves in a non-replicative yet viable phase, and the cell quantity drops. Cancer cells are described by unlimited cell growth and replication, thus displaying proliferative immortality. The procedure for metastasis and invasion is started after the interconnection of adhesion molecules to the extracellular matrix (ECM). The proteolytic enzymes are released by cells, and they exit the ECM, enter the bloodstream, and then are transported into the body [6]. Overall, these procedures correspond to the formation of the tumor microenvironment responsible for the maintenance and progression of cancer. In fact, the TME provides the best supporting system for cancers to grow. Therefore, combatting TME conditions seems to be a wise approach to cancer therapy.