A tumor is not only a collection of tumor cells, but also includes tumor cells, stromal cells, immune cells (lymphocytes, dendritic cells, monocytes/macrophages, granulocytes, mast cells, etc.) and various cytokines [45]. Stromal cells, immune cells and various cytokines constitute the tumor microenvironment and influence tumor growth and the therapeutic effects of drugs [46]. Various cytokines in the tumor microenvironment, such as interleukin-10 (IL-10), indoleamine-2,3-dioxygenase (IDO) [47], transforming factor-β (TGF-β) and chemokines, are immunosuppressive factors that inhibit the activation, migration and differentiation of immune cells [48]. Tumor cells produce large amounts of lactic acid during metabolism, and high concentrations of lactic acid affect macrophage polarization and immune function in tumor tissues. On the one hand, large amounts of lactic acid increase the expression level of the M2-type macrophage marker molecule type I arginase, reduce the M1-type macrophage marker molecule nitric oxide synthase and decrease M1-type cytokine secretion. High concentrations of lactate reduce the expression of MHC I and MHC II in tumor-associated macrophages, weakening the antigen-presenting ability of macrophages, thus helping tumor cells escape from immunological effects [49]. Moreover, the high presence of lactate in tumor tissues inhibits the proliferation of T cells, reduces the secretion of cytokine type II interferon (IFN-γ), suppresses the cytotoxic effects of CD⁸⁺ T cells [50] and NK cells [51], and weakens the immune function of the body. In addition, tumor cells inhibit the killing effect of cytotoxic T lymphocytes (CTL) by upregulating anti-apoptotic molecules, such as programmed death ligand-1 (PD-L1) and B lymphocytoma-2. PD-L1, which is expressed on the surface of dendritic cells and macrophages binds to the programmed death receptor (PD-1) on the surface of T cells, preventing the overactivation of T cells and diminishing the immune function of the body. Many tumor cells and tumor-associated cells also highly express PD-L1, inhibiting the immune response by the PD-1/PD-L1 pathway [47]. Stromal cells in tumor tissues can mediate T cell exocytosis, such as CXC chemokine ligand 12 produced by tumor-associated fibroblasts, which can lead to exocytosis of activated T cells from tumor tissues and reduce the number of tumor-infiltrating T cells [52,53]. In addition, tumor cells can express suppressive cytokines that recruit immunosuppressive cells including myeloid suppressor cells (MDSCs) and regulatory T cells (Tregs), which suppress the immune process of tumor cells [47].

All these factors create an immunosuppressive microenvironment in the tumor tissue, which leads to the continued growth of tumor cells escape the policing of the immune system. By contrast, certain poly(amino acid)s can regulate the immunosuppressive microenvironment by enhancing the immune response or counteracting the negative immunoregulatory effects of tumor cells. For example, R-methyltryptophan (D-1MT) can inhibit the recruitment of Treg and MDSC and increase the proportion of CD⁸⁺ T cells. L-Phenylalanine can restore T cell number and function by suppressing MDSCs. Poly(γ-glutamic acid) combined with chitosan can inhibit the polarization of macrophages to M2-type macrophages and promote T cell proliferation. At the same time, some positively charged poly(amino acid)s can mediate the antigen delivery by macrophages through electrostatic adsorption, which can lead to positive immune response and IL-12 release from macrophages. So use these poly(amino acid)s delivery system to regulate the immunosuppressive microenvironment to promote effective treatment of tumors. Wang et al. [54] synthesized four different configurations of block copolymers mPEG-PA by mPEG-NH₂-initiated ring-opening polymerization of alanine NCA with different chirality and investigated their sol-gel phase transition behavior. It was shown that poly-D-alanine induced T cell proliferation and differentiation and activated T cells by increasing the expression of TNF-α, IL-β and IL-6, which in turn generated a positive immune response. When it encapsulates tumor immunotherapeutic drugs to the tumor, it can improve immunotherapeutic efficacy by promoting immunomodulation. Yu et al. [9] used D-1MT, which can be oxidized by reactive oxygen species (ROS) as the raw material and synthesized a poly(amino acid)-based tri-block polymer (P(Me-D-1MT)-PEG-P(Me-D-1MT)) by ring-opening polymerization using PEG-NH₂ as the initiator. In the tumor microenvironment, the P(Me-D-1MT)-PEG-P(Me-D-1MT) hydrogel can release D-1MT, inhibiting the production of IDO, which lead to Treg and MDSC recruitment was inhibited and the proportion of CD⁸⁺ T cells was saliently increased. The expression of aPD-1 was also promoted by the D-1MT released to improve the patient's response to aPD-1 and prolong aPD-1 antitumor time, leading to the effect of aPD-1 tumor immunotherapy was enhanced. All of these factors overcome the immunosuppressive state of the tumor. Lim et al. [55] synthesized amphiphilic poly(L-lysine)-g-poly(L-phenylalanine) (PLL-g-Phe) by grafting poly(L-phenylalanine) (Phe) onto poly(L-lysine) (PLL) and prepared cationic polymeric NPs containing squalene (CASq) using nanoemulsion method. NPs exhibit a high drug-loading rate, good stability and good biocompatibility. In addition, NPs are positively charged in the tumor microenvironment. But cell membrane is negatively charged. So the NPs can mediate the antigen delivery by macrophages through electrostatic adsorption. Also, NPs can promote a positive immune response and IL-12 release from macrophages, which in turn can stimulate Th1-mediated immune response. Wu et al. [27] developed an L-phenylalanine polymer, which is called metabolic reprogramming immunosurveillance activation nanomedicine (MRIAN). MRIAN can degrade to L-phenylalanine, which can suppress PKM2 activity, inhibit the metabolism of glucose and reduce the level of ROS in MDSCs, significantly deregulating immunosuppressive functions, and inducing differentiation of MDSCs to immune cells that have functions, such as NK cells, macrophages, and DCs. Since MDSCs suppress T cell proliferation during tumor progression, MRIAN significantly restored T cell numbers and function by suppressing MDSCs to re-establish immunosurveillance in T-cell acute lymphoblastic leukemia(T-ALL) mice. Li et al. [56] developed a tumor microenvironments (TMEs)-adapted poly-peptide composite based on thermosensitive hydrogel and semi-deprotected poly(L-lysine) to sequentially deliver regorafenib and transform growth factor-β inhibitor. It is shown that poly(L-lysine) nanogel can reduce the recruitment of tumor-associated macrophages (TAMs) and MDSCs, increase tumor infiltration of CD⁸⁺ T cells, and promote the polarization of macrophages from M2 to M1 types, effectively inhibiting tumor growth. Castro et al. [57] synthesized chitosan/poly(γ-glutamic acid) nanoparticles (Ch/γ-PGA NP) from chitosan (Ch) and poly(γ-inhibited the polarization of macrophages to M2-type macrophages (Fig. 2A) and induced an immunostimulatory dendritic cell phenotype (Fig. 2B), promoting T cell proliferation and suppressing colorectal cancer cell invasion (Fig. 2C) [58].

Tumor growth depends not only on individual genetic mutations, but also on the inflammatory cells, immune cells, and blood vessels in the microenvironment. Uncontrolled inflammation is an important factor leading to changes in the tumor microenvironment, which is significantly correlated with tumor progression, invasion, and metastasis [59-61]. Tumors are called "incurable wounds" and pro-tumorigenic inflammation is one important mark of cancer [62]. Inflammation can be classified into two categories: acute and chronic. While acute inflammation is easily cured, chronic inflammation is not and can persist for a long time. A small percentage of chronic inflammation may turn into cancer, which is a vital cause of cancer development and has different functions along with tumor development [63]. For example, in viral hepatitis, the patient's infection is mostly acute at the beginning, when it can be cured with early treatment. However, if it is delayed or improperly treated or if the patient has an immune deficiency, it can lead to chronic inflammation. These chronic inflammatory diseases can cause cellular and tissue changes, and if not effectively cleared over time, they can develop into cirrhosis or even liver cancer. At the same time, viruses also stimulate infected cells and their surrounding cell to secrete inflammatory factors that alter the cellular microenvironment and promote cancer cell proliferation, infiltration, and metastasis. Certain inflammatory cells, like TAM, assist tumor cells proliferate by secreting growth factors, promote the development of new blood vessels by secreting vascular endothelial growth factor (VGEF) [64], accelerate tumor incursion of normal tissues and metastasis to other organs by secreting matrix metalloproteinases (MMPs) [65], and inhabit intrinsic and acquired immunity by secreting a variety of immunosuppressive factors such as interleukin (IL)-10 [66]. In addition, studies have demonstrated that certain inflammatory cells also render tumor cells resistant chemotherapy [67]. Löffler et al. [68] and Li [69] demonstrated that the pro-inflammatory cytokine IL-6 induced microRNA-21 expression in a STAT3 signaling pathway-dependent manner, facilitating tumor cell proliferation and suppressing apoptosis. Tili et al. [70] found that inflammatory stimulation upregulated microRNA-155 expression by transfecting in vitro cell cultures, which lead to the promotion of mammary cells proliferation and mutation. Both microRNA-155 overexpression and the inflammatory environment can downregulate WEE1 expression [71] and facilitate tumor cell proliferation.

Therefore, inhibiting inflammation at the tumor site is beneficial for effective cancer treatment. M1 and M2-type macrophages are important bridges between inflammation and cancer development and have a "double-edged sword" effect on tumors. M1-type macrophages can inhibit tumor growth while M2-type macrophages can promote tumor growth [72]. Among them, tumor-associated macrophages belong to M2-type macrophages, which are the main components of the tumor microenvironment, are important for tumor metastasis and can be potential targets for oncology therapy [73]. Therefore, certain poly(amino acid)s like can suppress the inflammatory response by inhibiting the inflammatory signaling pathway of macrophages, thus promoting the preferential treatment of cancer. Studies have shown that glycosylated poly(amino acid)s can be used for anti-inflammatory [74]. When the side chains of amino acid residues are attached to glycosyl groups to form nonionic water-soluble glycosylated poly(amino acid)s, the multivalent nature of their side chain glycosyl groups can enhance the affinity of poly(amino acid)s materials for protein receptors, which in turn can participate in vital activities such as molecular recognition and can also be used for inhibiting inflammation [75]. So we can construct drug delivery system with anti-inflammatory function based on glycosylated poly(amino acid)s. Bertozzi et al. [75] used a nickel metal catalyst with a lipid structure to initiate the ring-opening polymerization of glycosylated serine and alanine NCA, and introduced sialic acid and its derivatives to the side chain through an enzyme-catalyzed reaction, thus preparing a glycosylated poly(amino acid) with a lipid C-terminus. The glycosylated poly(amino acid) (pS9L) exhibited a high binding capacity to Siglec-9 and a high specificity for binding to the same cell surface receptor in "cis", which inhibit LPS-induced inflammatory signaling pathway in macrophages and inhibit the endocytosis of macrophage by regulating mitogen-activated protein kinases (MAPK) signal as Fig. S2 (Supporting information) shows. Although glycol-poly(amino acid)s are not currently used in the transport of anticancer drugs and effective treatment of cancer, it provides ideas for the treatment of cancer at the anti-inflammatory level and preventing tumor recurrence. Furthermore Wu et al. synthesized poly(ferulic acid) and poly(ursolic acid) with anti-inflammatory function ferulic acid and ursolic acid as hydroxy acid monomers, respectively, and studies have shown that poly(ferulic acid) [33] and poly(ursolic acid) [34] still have anti-inflammatory function. Therefore, the polymers basing on amino acid monomers with anti-inflammatory functions such as glutamine, tryptophan and their derivatives may also have anti-inflammatory functions, which can be used as anti-cancer drug carriers to exert drug delivery and anti-inflammatory functions. It also provides ideas for synthesis of poly(amino acid) carriers with anti-inflammatory functions.

ROS are atoms, groups of atoms or molecules with unpaired electrons generated during cell metabolism, which are highly unstable and short-lived, such as superoxide anions (O²⁻) and hydrogen peroxide (H₂O₂) [76,77]. The abnormally active metabolism of tumor cells consumes a large amount of oxygen, making the tumor usually in a hypoxic environment. Hypoxia leads to more ROS production in mitochondria [78], which causes mutations in base pairs and DNA mainly by changing the structure of single or double strands DNA, leading to abnormal activation of gene mutations in tumor cells [79] and inactivation of tumor suppressor genes [77,80]. ROS can cause abnormal mitosis in cells and induce the transformation of normal cells to tumor cells [81]. ROS can regulate extracellular-regulated protein kinases (EKP) by shifting the inhibition of MAPK phosphatase through oxidative stress. Then the P13/Akt and ERK signaling pathways are activated, increasing the endogenous level of ROS production and the expression levels of antioxidants by repressing various transcription factors of FOXOs. Antioxidants such as nuclear factor erythroid 2-related factor 2 (NRF2) and TIGAR inhibit ROS-mediated cell death and promote tumor development (Fig. 3). In addition, ROS oxidize the tumor tissue matrix and help tumor cells metastasize [82], and the presence of large amounts of ROS inhibits T cell activation, creating an immunosuppressive tumor microenvironment that allows tumor cells to escape immune killing [83]. Meanwhile, continuous production of ROS can stimulate neovascularization to help tumor cells obtain more nutrients and facilitate tumor cell metastasis [84,85]. However, tumor cell death occurs when ROS levels are too high [86]. Therefore, tumor cells are sensitive to loss of antioxidant capacity due to reduced NADPH production, such as reduced oxidative pentose phosphate pathway (oxPPP) activity, reduced carboxylation and increased mitochondrial ROS (mtROS) production due to the inhibition of tumor cell aggregation (Fig. 3). In some cases specific anti-tumor immunity is activated due to ROS-induced tumor cell death [87]. In conclusion, although ROS can cause damage and reduce cell viability to some extent in almost all cell types, including tumor cells [88]. It is worth noting that the high tolerance of tumor cells will gain more benefits in a state of oxidative stress, and several studies have shown that high ROS expression often occurs in malignant tumor lesions in vivo, suggesting a close "tumor-ROS" tandem effect, promoting tumor growth and metastasis [89], so antioxidant therapy may bring more benefits for tumor treatment.

The main purpose of antioxidants is to prevent the accumulation of excess ROS and to remove excess ROS. Certain poly(amino acid)s can consume ROS through chemical reactions to achieve antioxidant effects and promote effective cancer treatment, such as poly(amino acid)s based on L-methionine, which are easily oxidized by ROS to methionine sulfoxide because of the thioether bond contained in methionine, which reduces ROS, so most poly(amino acid)s with antioxidant functions are based on methionine. Yu et al. [9] used L-methionine and D-1MT, which can be oxidized by ROS, as raw materials and synthesized poly(amino acid)-based tri-block polymer (P(Me-D-1MT)-PEG-P(Me-D-1MT)) hydrogels via ring-opening polymerization with macromolecular PEG-NH2 as the initiator. The P(Me-D-1MT)-PEG-P(Me-D-1MT) hydrogel can be injected in-situ in tumors and has a biostimulatory response to drug release. It shows that the hydrogel can effectively reduce ROS levels in the cellular microenvironment. Quan et al. [90] synthesized an ROS-responsive poly(ethylene glycol)-poly(methionine) (PEG-P(Met)), which can deliver the pro-oxidant drug piperlongumine (PL) to cancer cells safely and effectively. It can reduce ROS through the oxidation of the thioether bond contained in methionine. Zhao [91] prepared methionine as an active monomer that could be polymerized in situ, and then triggered the polymerization of the active monomer with a four-armed poly(ethylene glycol)-amino group as initiator to obtain block polypeptides, which could form stable hydrogels in aqueous solution, and the hydrophobic interactions between their blocks formed reversible physically cross-linked hydrophobic micro-regions within the hydrogels, making them available to encapsulate the hydrophobic anticancer drug and as a drug carrier to achieve slow release of the drug to promote effective cancer treatment. It was shown that in the tumor microenvironment with large amounts of ROS, methionine on the poly(methionine) side chain could be oxidized, resulting in a reduction of ROS in the tumor microenvironment. Xu [92] synthesized Met-based PEA and then conjugated PEG to the ends of the Met-PEA chains to synthesize amphiphilic polymers that can be autonomously loaded as nanoparticles. The nanoparticles include a hydrophobic Met-PEA core that can accommodate hydrophobic anticancer drugs, which have a hydrophilic PEG hull that reduces protein absorption from the blood on the outside of the nanoparticles and prolongs the blood circulation time. When the sulfhydryl group in cysteine is attached to the glycoside, thioether bonds are present in the polymer, which can also clear ROS via an oxidation. For example, Deming et al. [93] synthesize side-chain glycosylated poly(cysteine) by NCA ring-opening polymerization, which has thioether that can react with ROS, so it can be used to deliver anti-cancer drugs and exert its antioxidant ability to promote effective treatment of cancer.

The proton sponge effect refers to the ability of the lysosome to trap a large number of protons when the pH in the lysosome drops causing an inward flow of Cl⁻ and water molecules, resulting in osmotic swelling of the lysosome. The particles with cations bind to the cell membrane and enter the cell through endocytosis and then form endosomes, which fuse with the lysosomes (Fig. S3A in Supporting information). The unsaturated amino groups on the particles chelate the protons provided by the proton pump, which is continuously open, leading to a continuous proton influx. To prevent further acidification and balance the charge within the lysosome, each proton leads to the retention of one chloride ion and one water molecule in the lysosome (Fig. S3B in Supporting information), triggering lysosomal swelling and rupture (Fig. S3C in Supporting information) [94,95]. However, the rupture of lysosomes allows the entry of the encapsulated drug into the cytoplasm, while the spillover of lysosomal contents and release of intracellular Ca²⁺ lead to cytotoxicity [96]. The spillover of lysosomal enzymes can contribute to the activation of certain proteins, which in turn can damage mitochondria. Triggering of Ca²⁺-regulated permeability transition pores in mitochondria also leads to reduced ATP production and cell apoptosis [94].

Certain amino acids such as lysine, arginine, leucine, and histidine are positively charged. Therefore, drug carriers containing these amino acids can promote apoptosis of tumor cells through the proton sponge effect and facilitate effective cancer therapy. Chang et al. [23] synthesized a pH- and ROS-responsive drug delivery system. Paclitaxel and glucose were coupled to a paclitaxel polymer precursor (DEX-TK PTX) via a bond that could be cleaved by ROS. Subsequently, poly(L-histidine) (PHis) and Lapa were packaged in micelles formed by DEX-TK PTX to construct the drug delivery system PLP NPs. These PLP NPs have good biocompatibility, long cycle time and can accumulate in tumor tissues because of the enhanced permeability and retention (EPR) effects. PLP NPs can enter cancer cells via the endocytic pathway and are later delivered into the lysosome, where PHis are protonated in the acidic environment of the lysosome, leaving the proton pump continuously open, leading to the passive entry of chloride ion and water molecules into the lysosome, causing the lysosome to swell and rupture. Various enzymes within lysosomes are released into the cytoplasm, promoting mitochondrial damage and apoptosis in tumor cells. Yi et al. [25] synthesized an intelligent multi-stage tumor-targeting drug carrier based on n-butylamine-poly(L-lysine)-b-poly(L-cysteine) (PLL-PLC), and then functionalized it with folic acid (FA) and 1,2-dicarboxylic acid cyclohexene anhydride (DCA). Combining FA with poly(L-lysine) fragment enhances the tumor targeting ability. Grafting DCA on poly(L-lysine) fragment can make nanoparticles maintain negative charge under normal physiological conditions but rapidly convert to positive charge under the tumor microenvironment, the charge reversibility of nanoparticles can not only improve their blood circulation stability, but also provide excellent "proton sponge" effect, which promotes the absorption of drugs in tumors and the escape of endosomes, promoting the delivery of tumor-targeted drugs and apoptosis of tumor cells.