The cancer immunosurveillance concept, i.e., the opinion that the immune system could recognize and destroy nascent malignant tumor cells, was first conceptualized by Burnet and Thomas in the twentieth century [14]. However, due to a lack of convincing evidence, this theory was largely ignored for the decades that followed. With better understanding of tumor antigens and the establishment of a completely immunodeficient mouse model, an abundant body of data was generated, which supported the existence of immunosurveillance, rekindling interest in this process. Further research showed that tumors were being modified by the immune environment, which resulted in tumor cells of high immunogenicity being killed by the immune system, but the weakly immunogenic ones being ignored, while simultaneously acquiring other mechanisms for immune evasion. These processes may be due to the inherent genetic instability and rapid adaptability of tumors [15]. New tumor cell variants with reduced immunogenicity are continuously produced and cleared to form a kind of equilibrium. Eventually, the immune system is impaired by the constant stimulation of tumor cells and the balance is upset. It is during this stage that tumor escape occurs and a tumor may progress to clinical relevance. Dunn et al. concluded that three sequential phases exist during interactions between tumors, immune cells, and the tumor microenvironment (TME): elimination, equilibrium, and escape [15,16]. These breakthroughs in the comprehension of tumor immune biology have opened a new chapter in the war against cancer in the new millennium.

Malignant cells escape from host immune responses via complex mechanisms (Figure 1). Tumor-specific antigens (TSAs) are regarded as vital cornerstones in immunotherapy, consisting of tumor-associated antigens (TAAs), oncogenic viral antigens, and neoantigens, that can sufficiently induce both humoral and cell-mediated immunity. The “ideal cancer antigen” should have highly specific overexpression only in tumor cells, and immunogenicity which could mount a robust immune response. Alas, internal tumor antigens exist, which are usually weakly immunogenic, or develop mechanisms to avoid presentation on the surface of antigen presenting cells (APCs) [17], which fail to activate specific cytotoxic T lymphocytes (CTLs) against tumors. Apart from this, several suppressive factors in the TME can cause immune tolerance and immune deviation, such as: upregulation of immune checkpoints (ICPs) on the tumor cell and immune cell surfaces, low secretion of immune costimulatory molecules, imbalance of the T helper lymphocyte (Th) 1:Th2 ratio, and production of immunosuppressive cytokines. Further to this, immunosuppressive cells can be recruited. These can include regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). In addition, chronic inflammation could also stimulate tumor progression [18]. Nutrient competition, including for glucose, amino acids, and fatty acids in the TME can also impact T-cell function and cause T-cell hyporesponsiveness [19,20].

The immune system and cancer progression are both highly intricate and heterogeneous, increasing the complexity in immunotherapy. Early on, scientists paid more attention to enhancing the antitumor immune response in quantity and/or quality. This strategy could be subdivided into two groups. The first approach is passive immunotherapy, which utilizes effector cells and/or molecules of the immune system for direct tumor attack, such as monoclonal antibody and antibody-drug conjugate therapy (ADC), adoptive cell therapy, and genetically engineered T cells (chimeric antigen receptor [CAR]-T, T-cell receptor [TCR]). These passive strategies can boost host immune responses against tumor at a high level. The second approach is active immunotherapy, which can enhance endogenous immune response against tumors. The representatives are antigen/adjuvant vaccines and dendritic cell (DC) vaccines, which can enhance antigen uptake, processing, and presentation to T cells by APCs. This could also extend to cytokines or agents that promote the activity of APCs, such as type I interferons (IFNs), Toll-like receptor (TLR) agonists, and stimulators of interferon genes (STINGs). Although a broad range of applications of the above strategies against various cancers have acquired Food and Drug Administration (FDA) approval, there is only a small proportion of patients, mainly suffering from classical immunogenic tumors, who can benefit from these therapies. Moreover, these immune-enhancing treatments can lead to serious immune-related adverse events (irAEs), such as some off-target toxicities and acute cytokine release syndrome, since the immune system is in supraphysiological level [20,21]. Introduction of these new compounds is accompanied by new side effects which are often mild or moderate, but may be severe and life-threatening, demanding adjustment and development of better therapies or strategies to overcome adverse effects [22,23].

With a deeper understanding of immune escape mechanisms, more explorations emphasize correction of the particular defects or dysfunctions present during tumor progression, and aim to correct or modify blocked antitumor immune responses in comparison with enhancement strategy. Sanmamed and Chen described this shift of immunotherapy strategy as “the age of normalization cancer immunotherapy”. Anti-programmed death receptor (PD) therapy is a typical example of undoing the immune suppression within the TME and has been approved by the FDA for the treatment of various malignant tumors beyond those classically considered immunogenic tumors. Clinical studies show more frequent objective tumor responses than severe irAEs. These exemplify the move within novel cancer immunotherapy strategies, from traditional immune enhancement approaches to immune normalization [21].

Nano-immunotherapeutics can have a range of targets and applications due to a large amount of tailorability. Shi and Lammers documented three primary ways to achieve tumor reduction via cancer nano-immunotherapy, over and above direct cytotoxicity [2]. These include cancer cell targeting, immune microenvironment alteration, and peripheral immune system targeting. It is agreed that recent progress made in all three of these areas is indicative of the significant potential held by combinational nano-immunotherapy to improve treatment outcomes in patients [24]. Below, the common applications of nanomaterials in immune therapy are summarized (Figure 2). Excellent reviews exist on the topic [25,26,27], but are beyond the scope of this paper, so only an overview will be provided. We wish to emphasize that the areas of application of liposomes are ideal for cancer immunotherapy: immune induction, synergistic therapy, and drug delivery and targeting [26]. These major strengths are further bolstered by low inherent toxicity [28], earning much clinical interest in recent years [29].

Liposomes are uni- or multilamellar lipid-based vesicular nanoparticles, made up of a phospholipid bilayer encapsulating an internal milieu [30]. Liposomes were first described in 1964 [31], and utilized as drug delivery systems in 1971 [32]. By virtue of the structures of utilized phospholipids, there exist distinct hydrophobic and hydrophilic regions in the core of the liposome and within the lipid bilayer, respectively. Phospholipid bilayers tend to measure approximately 4 nm and liposomes are known by different classifications based on the size and geometry thereof [33]. If multiple lamellae are enclosed in an outer membrane, a liposome is known as a multilamellar vesicle (MLV), whereas single-lamella liposomes, enclosing only a hydrophilic internal milieu, are known as small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), or giant unilamellar vesicles (GUVs) due to size; <100 nm, >100 nm, and >1 µm, respectively. This article will address the application of immunoliposomes in the treatment of cancer; therefore, the term liposome, for the purposes of this paper, refers primarily to SUVs. Advantages and disadvantages of liposomes are summarized in Table 1.