Perineural invasion in digestive tract tumors: Immune system interactions and therapeutic strategies

Table 1 Immune mechanisms driving perineural invasion in digestive tract tumors

Molecules		Immune role	Similar role in EC, GC, and CRC with PNI	Different roles in EC, GC, and CRC with PNI
Immune cells	CD8+ T cells	Recognize and kill tumor cells	Act as key immune regulatory cells in the PNI process; the number of infiltrating cells and their functional status are directly associated with patient prognosis; when functioning normally, they can inhibit the perineural invasive ability of tumor cells; when functionally impaired, they promote the occurrence of PNI	EC: Their antitumor function is significantly suppressed by PD-L1 in the tumor microenvironment and other immunosuppressive factors, increasing the risk of PNI; GC: Their function is impaired due to the PD-L1-mediated immune checkpoint pathway and factors such as hypoxia and lactic acid accumulation in the tumor microenvironment, failing to effectively prevent tumor perineural invasion; CRC: Dysfunction occurs due to abnormal activation of the PD-1/Notch signaling pathway; the density of infiltration and functional status can serve as important indicators for predicting the occurrence of PNI[54]
	Tregs	Express FOXP3, exert immunosuppressive effects, suppress effector T-cell activity	Promote immune escape, alter frequency/function related to PNI[49,50]	Not mentioned
	B cells	Antitumor immune response by producing antibodies	Mediate the PNI process through antibody responses; for example, abnormal antibody secretion may affect the integrity of perineural tissues or promote the adhesion of tumor cells to nerves; interact with other immune cells in the tumor microenvironment to jointly regulate the perineural invasive behavior of tumor cells[51,52]	GC: The ability to produce antibodies is reduced, leading to weakened humoral immune surveillance against tumor cells and increased susceptibility to PNI; EC/CRC: No specific differential roles related to PNI mentioned
	NK cells	Directly kill tumor cells	Provide cytotoxicity against tumor cells; when their function is impaired, the ability to clear tumor cells is reduced, which facilitates tumor cells to invade nerves and promotes PNI; the functional status of NK cells in the tumor microenvironment is an important factor affecting the occurrence of PNI[51,52]	EC: The activity of NK cells is significantly impaired and their killing effect on tumor cells is weakened, which is conducive to the perineural invasion of tumor cells[55]; GC: The cytotoxicity of NK cells is reduced, making it difficult to effectively inhibit the growth and nerve invasion of tumor cells; CRC: Dysfunction of NK cells is frequent, and the abnormal function is closely related to the high incidence of PNI[56]
	DCs	Antigen presentation and T-cell activation	Play a role in T-cell priming in the PNI process; when DCs function normally, they can effectively activate T cells to inhibit tumor nerve invasion; dysfunction of DCs leads to insufficient activation of the adaptive immune response, creating conditions for tumor cells to invade nerves and promoting PNI[51,52]	GC: The antigen-presenting capacity of DCs is reduced, resulting in weakened activation of T cells and inability to form an effective antitumor immune response, thereby promoting PNI; EC/CRC: Not mentioned
	Macrophages	Exhibit dual functional phenotypes (antitumor M1 vs protumor M2) in the TME; associated with PNI	Assist in tumor nerve infiltration, mainly through the M2 protumor phenotype; M2 macrophages can secrete factors that promote tumor cell invasion and damage perineural tissues, thereby facilitating PNI; the polarization direction of macrophages in the TME affects the progression speed of PNI[51,52]	EC: Macrophages tend to exhibit protumor phenotypes; they can secrete enzymes (e.g., matrix metalloproteinases) to degrade perineural matrices, providing channels for tumor cells to invade nerves; CRC: Macrophages play context-dependent dual roles; in some microenvironments, they support the antitumor immune response to inhibit PNI, while in other contexts, they promote tumor cell invasion to accelerate PNI; GC: No specific differential roles related to PNI mentioned[56]
Immune checkpoints	PD-1/PD-L1 axis	Tumor immune escape, suppresses T cells	Promotes PNI; poor PNI prognosis[53,55]	EC: Binds PD-1 to suppress T cells (correlates with extensive PNI)[57,58]; GC: Upregulated by CD8+ cell-derived IFN-γ (enables immune escape)[59]; CRC: Elevated on tumor/immune cells (associates with extensive PNI)[60]
	PD-L1	Binds to PD-1 on T cells inhibiting T-cell activity helping tumor cells evade immune attack	Inhibits T-cell activation, weakening the body’s ability to clear tumor cells, thereby creating favorable conditions for tumor cells to invade nerves and promoting PNI[54]	GC: Contributes to T-cell suppression; the high expression of PD-L1 on tumor cells significantly inhibits the function of infiltrating T cells in the TME, promoting PNI; EC/CRC: No specific differential roles related to PNI mentioned[61]
	PD-1	Affects T-cell function, decreased immune surveillance	Synergizes with PD-1 to enhance immunosuppression, worsen PNI[54]	EC: Particularly relevant (T-cell exhaustion, potential therapeutic target)[61]; GC/CRC: No prominent role noted
	CTLA-4	Reduces antitumor immune response efficiency, a different mechanism from PD-1/PD-L1 axis	Collaborates with other immune checkpoints (e.g., PD-1/PD-L1) to suppress T-cell function; the combined inhibitory effect further weakens the antitumor immune response, promoting the occurrence of PNI[54]	CRC: Synergizes with PD-1; the combined blockade of CTLA-4 and PD-1 can more effectively restore T-cell function, improve the antitumor immune response, and thus improve the prognosis of patients with PNI[61]; EC/GC: Not mentioned
	TIM-3	An immunosuppressive molecule affects T-cell function	Aids in T-cell exhaustion and tumor immune escape; the activation of TIM-3 leads to the loss of T-cell immune function, making it easier for tumor cells to invade nerves and promoting PNI[53,54]	EC: Promotes the traits of CSCs (e.g., self-renewal, invasiveness) and enhances the invasive ability of tumor cells; indirectly aids the perineural invasion of tumor cells by regulating CSC function and immune cell activity[61]; GC/CRC: Not mentioned
	LAG-3	Together with CTLA-4 and TIM-3, it inhibits tumor-reactive T-cell stimulation and proliferation, and T-cell dysfunction	Cooperates with PD-1 to inhibit T cells, aids PNI[53,54]	CRC: Synergizes with PD-1 to suppress T cells; combined blocking of LAG-3 and PD-1 shows promise for improving PNI outcomes[60]; EC/GC: Synergistic effect with PD-1 is less prominent in PNI
Immune-related factors	IFN-γ	Dual-role: Activates immune cells and enhances immune surveillance; induces tumor cells to express PD-L1, disrupting immune balance	Affects the balance of PNI; on one hand, it enhances immune surveillance to inhibit tumor nerve invasion; on the other hand, it promotes tumor immune escape by inducing PD-L1 expression, thereby facilitating PNI; the final effect depends on the relative intensity of the two roles[58,59]	GC: Upregulates the expression of PD-L1 on tumor cells; the high expression of PD-L1 enables tumor cells to evade the attack of T cells, promoting the perineural invasion of tumor cells[59]; EC/CRC: No specific role noted
	TGF-β	Modulates TME immunosuppression, regulates immune cell function	Exerts protumor and immunosuppressive effects; disrupts the immune homeostasis in the TME, weakens the antitumor immune response, and creates favorable conditions for tumor cells to invade nerves, thereby promoting PNI[56,57]	EC: Suppresses immunity, modulates immune-cell phenotypes, promotes nerve invasion; CRC: Role more prominent vs EC/GC; it can strongly regulate the TME and tumor cell behavior to accelerate PNI[50,62]
	Notch signaling	CSCs’ differentiation and self-renewal affect immune cell function	Promotes the traits of CSCs (e.g., self-renewal, invasiveness) and enhances the invasive ability of tumor cells; indirectly aids the perineural invasion of tumor cells by regulating CSC function and immune cell activity[61,62]	CRC: Promotes the traits of CSCs (e.g., self-renewal, invasiveness) and enhances the invasive ability of tumor cells; indirectly aids the perineural invasion of tumor cells by regulating CSC function and immune cell activity[63]; EC/GC: Not mentioned
	Hedgehog signaling	Active in CD133-positive CSCs	Regulates the crosstalk between tumor cells and nerves; promotes the perineural spread of tumor cells by mediating the communication between tumor cells and nerve cells[56,57]	GC: Drives the crosstalk between tumor cells and nerves; directly promotes the perineural invasion of tumor cells by regulating the expression of factors related to nerve invasion[61]; CRC: Is active in CD133+ CSCs, but the crosstalk between tumor cells and nerves mediated by this pathway is weak, and its role in PNI is less prominent[52]; EC: No specific tumor-nerve crosstalk role in PNI
	VCAM1	Related to PD-L1 expression, tumor immune escape	Regulates the expression of PD-L1 and the recruitment of immune cells; promotes tumor immune escape, thereby creating conditions for tumor cells to invade nerves and facilitating PNI	GC: Contributes to tumor immune evasion; regulates the expression of PD-L1 on tumor cells and the recruitment of immunosuppressive cells (e.g., Tregs) in the TME, thereby promoting PNI[62]; EC/CRC: Not mentioned
	CCL2	Mediates inflammatory cell recruitment, attracts macrophages	Recruit macrophages and inflammatory cells to the perineural area; damages perineural tissues by regulating the inflammatory response; drives the perineural invasion of tumor cells[63]	EC: Establishes a pro-invasive perineural niche; recruit macrophages and other inflammatory cells to the perineural microenvironment, creating a microenvironment conducive to tumor nerve invasion[62]; GC/CRC: Not mentioned
	IL6/STAT3 signaling pathway	Related to VCAM1 and PD-L1 expression, it disrupts the immune balance	Regulates the recruitment of immune cells and the expression of PD-L1; promotes tumor immune escape, thereby facilitating the perineural invasion of tumor cells and promoting PNI	CRC: Sculpts the immunosuppressive TME; modulates the expression of PD-L1 on tumor cells and the function of immune cells (e.g., inhibits the cytotoxicity of CD8+ T cells); cooperates with other pathways to promote the perineural invasion of tumor cells[63]; EC/GC: Not mentioned

EC: Esophageal cancers; GC: Gastric cancers; CRC: Colorectal carcinoma; PNI: Perineural invasion; PD-L1: Programmed death ligand 1; PD-1: Programmed death 1; Tregs: Regulatory T cells; FOXP3: F-box and leucine-rich repeat protein 3; NK: Natural killer; DCs: Dendritic cells; TME: Tumor microenvironment; IFN-γ: Interferon-γ; TGF-β: Transforming growth factor-β; CTLA-4: Cytotoxic T lymphocyte-associated protein 4; TIM-3: T-cell immunoglobulin and mucin 3; LAG-3: Lymphocyte activation gene-3; CSCs: Cancer stem cells; VCAM1: Vascular cell adhesion molecule 1; CCL2: Chemokine ligand 2; IL6: Interleukin-6; STAT3: Signal transducer and activator of transcription 3.