Many clinical pathologies have improved immuno-therapeutic applications by the use of polymeric nanomaterials. However, understanding the mechanisms behind cancer immunity is an urgent need for deciding on suitable strategies for cancer immunotherapies [43,44]. In recent years, advancements in polymer science and nanotechnology have provided approaches to improving cancer immunotherapies. Multidisciplinary fields bridging chemistry, physics, biology, engineering, and medicine have helped design, synthesize, and characterize nanomaterials and extend their applications in various immunotherapies. Upon considering this, the biomedical investigations and the rapid developments of polymer-based nanoparticles and their deep understanding in medical fields have resulted in their clinical applications, including in cancer treatment. The potential of polymeric nanoparticles is extensive due to their unique and multifaceted functions, including adjustable surface area, easy tunability for cell-materials, and cell–chemical–biological interactions to accommodate higher drug contents during drug delivery applications [45]. The prominent phenomenon of polymeric nanoparticles is the easy surface functionalization for achieving precise target-tissue biodistribution and blood clearance upon circulation [46]. In addition, polymeric nanoparticles could also exhibit different functionalities via the incorporation of theranostic molecules such as fluorescent probes, drug conjugates, or antibody–drug conjugates. These molecules can be easily coupled onto the surfaces of the polymeric biomaterials [47,48].

The use of polymeric nanoparticles combined with metal nanoparticles to deliver cancer immunotherapies has already been approved for clinical applications and many are currently undergoing clinical trials [49]. The organic and inorganic nano biomaterials possess higher biocompatibility with reduced side effects when modified with bio-functional polymers. In addition, several organic nanoparticles with polymeric modifications have been under investigation for clinical applications as vaccines, as a means to prolong drug delivery systems, and as biocompatible dermal and tropical drugs. Likewise, the intravenous delivery of organic nanomaterials is also efficiently utilized for cancer immuno- and gene therapies [50,51]. Organic nanomaterials with the modifications of polymer materials, especially for immunotherapy, have shown broader and more prolonged success rates in preclinical models because of their increased biocompatibility with targeting efficiency [52]. Despite these, the biologically engineered polymer nanomaterials modified with organic polymers have demonstrated long-term safety with less accumulation in clearance organs such as the kidney, liver, and spleen. Hence, the utilization of polymer-based engineering approaches to make multifunctional nanoparticles has evolved to show promising delivery vehicles with increased drug loading capacity, controlled delivery, antibody targeting, and targeted accumulation at the localized TMEs as switchable candidates during therapeutic applications [53]. Upon considering all these factors, designing a polymer nanoparticle-based vaccine will always require an antigen as a primary vital content that is generally present in a short-peptide form to trigger the adaptive host immune responses [54]. Moreover, a long-lasting and robust immune response could also be achieved through natural killer (NK) cells [55]. Thus, developing the polymeric vaccine as a potential cancer immuno-therapeutic agent to effectively internalize via tumor homing and penetration through cell membranes is of immediate need for expanding this field in cancer immunotherapies.

The prerequisite of polymeric nanoparticles in cancer immunotherapy is to induce many signaling events of cancer cells to achieve treatment outcomes [56,57]. The cancer immunity cycle (Figure 2) plays a significant role in activating immunotherapy responses in the tumor to remove cancer cells or alter the TME by releasing tumor antigens. Upon delivery of polymeric nanoparticles to the tumor site, the cancer cells undergo numerous biological changes to induce apoptosis-mediated cell death pathways and release cancer antigens for further immune activation to induce CTL responses. The released cancer cancer-specific antigens are presented by the antigen-presenting cells (APCs) in the context of the major histocompatibility complexes (MHCs) [58]. MHCs play a prime role in the immune system by enhancing the modulatory functions in the infected cells during vaccination. MHCs have a highly pronounced cell surface display of intracellularly derived proteins and peptides for immune activation. Furthermore, the MHCs presenting dendritic cells (DCs) and tumor antigens stimulate the activation of immature T-cells in the lymph node to trigger the tumor-specific CTLs and natural killer (NK) cells which allow them to control cellular events and identify TMEs in tumorigenesis [32,59,60]. CTLs effectively communicate with the T-cell signaling molecules of the receptors and MHCs to attract tumor cells.

Furthermore, polymeric nanoparticles facilitate T-cell-mediated cellular apoptosis, which eventually stimulates the release of cancer antigens to boost further immune responses [45,50,60]. This could maintain the events that promote specific immunity to cancer, which can also be disturbed through multiple barriers that reduce the immuno-therapeutic mechanisms. In addition, the pro-inflammatory responses from the polarized macrophages (M1) [61] are highly involved in regulating and killing tumor cells via the production of immunosuppressive cytokines [62]. As shown in Figure 3, the various forms of delivered polymeric nanomaterials can facilitate the internalization of APCs through modulating migration, uptake, and maturation in the weakly acidic TMEs. This could further enable the production of tumor antigens that enhance NPs’ immunomodulatory potential, such as through reducing regulatory T-cell population, DC activation, and macrophage repolarization (M2 to M1) to induce immunogenic cell death (ICD). These actions are potentiated in the TMEs through the regulation of various cytotoxic T-cell-associated immune modulations and encouraging immunotherapies (Figure 2 and Figure 3). Immunosuppressive candidates such as PD-1, PD-L1, and CTLA-4 are involved in decreasing tumor cell proliferation. These conditions may be involved in reducing the immuno-therapeutic efficiencies that are the cause of the existing problems with current cancer immunotherapies [63,64]. Nanomaterials, including polymeric nanoparticles could intervene in these conditions, to boost cancer immunity towards successive immuno-therapeutics [65,66].