Abbreviations: irAEs, immune-related adverse events; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis; ICIs, immune checkpoint inhibitors; anti-CTLA-4, anti-cytotoxic T-lymphocyte antigen 4; anti-PD-1, anti-programmed cell death 1; anti-PD-L1, anti-programmed cell death-ligand 1; HLA, human leukocyte antigen.

3.1. Morbilliform (Maculopapular) Eruption

The morbilliform eruption is the most commonly observed cutaneous irAE. It affects approximately 49–68% of patients undergoing anti-CTLA-4 therapy and 20% of patients receiving PD-1/PD-L1 inhibitors ^[13][21][13,47]. Typically, the morbilliform rash occurs within the first three to six weeks after initiating ICIs treatment ^{[10][12][22][23]}[10,12,48,49]. Clinical presentations include pruritic faint erythematous macules and papules that coalesce into plaques. It primarily affects the trunk and the extensor side of the extremities, while the head, palms, and soles are usually unaffected ^[13][14][13,14]. Histopathological examinations reveal interface changes and perivascular or periadnexal lymphocytic infiltration, with or without eosinophils. Although maculopapular rashes are usually mild and resolve on their own, they can occasionally serve as an initial presentation of severe cutaneous adverse reactions like SSJS/TEN or DRESS. The detailed mechanisms of ICI-induced morbilliform eruption remains unclear, but there is a hypothesis suggesting an association with type IVc hypersensitivity reactions ^[12][24][12,50], in which cytotoxic T cells act as effector cells. Under immunotherapy, activated cytotoxic T lymphocytes can directly harm target cells by releasing cytotoxic cytokines, including perforin, granulysin, either granzymes or granzymes B, and through physical interaction via the FasL/FasR pathway. Moreover, type IVc hypersensitivity is also predominantly implicated in SJS/TEN ^[24][25][50,51].

3.2. Pruritus

Pruritus is another common cutaneous irAE associated with ICIs. It can occur in conjunction with other skin manifestations or as an isolated symptom. Studies have indicated that pruritus affects approximately 14% to 47% of patients receiving ICIs, with higher incidence rates seen in those receiving anti-CTLA-4 monotherapy (25–36%) and combination therapy (33–47%) ^[12][17][12,43]. Typically, pruritus manifests within one to twenty-seven weeks after starting therapy and is commonly observed on the scalp and trunk, while the face, anterior neck, genitalia, and soles are usually unaffected ^[11][26][27][11,52,53]. In most cases, pruritus induced by ICIs is of low severity, and less than 2% of patients develop refractory high-grade pruritus ^[28][29][54,55]. The most extensively studied cytokines in the pathogenesis of itch are Th2 cytokines, including IL-4, IL-13, and IL-31. Certain Th1 cytokines, such as IL-17, may also be involved in psoriasis-related itch. Therefore, pruritus induced by ICIs may result in Th1/Th2 dysregulation, leading to the production of cytokines that promote skin inflammation ^[30][31][56,57]. However, the precise mechanism of ICI-related pruritus is not yet fully understood. Genetic differences in human leukocyte antigen (HLA) haplotypes have been implicated in predisposing patients to develop irAEs. As a result, it is believed that genetic factors play a role in the pathogenesis of irAEs. Some irAEs closely resemble established autoimmune disorders that are associated with specific HLA risk alleles. For example, ICI-related colitis has been linked to HLA-DQB1*03:01 ^[32][33][58,59], ICI-induced hypothyroidism to HLA-DR8 ^[34][60], and ICI-related arthritis to HLA-DRB1*04:05 ^[35][61]. Similarly, specific HLA alleles have been found to be associated with ICI-induced pruritus, such as HLA-DRB1*11:01, as reported in several studies ^[33][36][59,62]. Despite extensive investigations, the exact mechanism linking HLA variants to irAEs remains elusive.

3.3. Lichenoid Eruptions

Lichenoid eruptions are more prevalent in patients receiving PD-1/PD-L1 inhibitors compared to those receiving CTLA-4 inhibitors ^{[13][21][37][38][39][40]}[13,47,63,64,65,66]. These eruptions usually occurs between six to twelve weeks after initiation of ICI therapy ^[11][12][11,12], affecting less than 17% of patients using anti-PD-1 agents ^[41][67]. Clinical manifestations of lichen planus (LP) are characterized by shiny, flat-topped, polygonal, erythematous to violaceous papules and plaques with a thin, white lacelike pattern (Wickham striae) on the surface of the lesions, and it often exhibits symmetrical distribution on the flexural areas of the extremities. In contrast, ICI-associated lichenoid eruptions are pruritic, multiple, often grouped and confluent, purple-colored, flat-topped, slightly keratotic papules, or plaques mostly on the extensor surfaces of extremities and the trunk. Moreover, unlike lichen planus, ICI-induced LP-like eruptions are less frequently involved in the genital or oral mucosa, and Wickham striae are usually absent ^{[13][42][43][44][45][46][47][48][49]}[13,68,69,70,71,72,73,74,75]. Both lichen planus (LP) and lichenoid eruptions share common histopathological findings, such as interface changes characterized by a dense band-like superficial infiltration of lymphocytes, a saw-tooth rete ridge pattern, hyperkeratosis, hypergranulosis, and the presence of apoptotic cells in the basal layer of the epidermis. However, in ICI-induced LP-like eruptions, there are additional distinctive features, including focal spongiosis, parakeratosis, focal interruption of the granular layer, and the presence of eosinophils or necrotic keratinocytes ^[13][42][43][13,68,69]. Furthermore, rare variants of LP, including ulcerative LP ^[44][70], hyperkeratotic LP ^[45][71], inverse LP ^[46][72], bullous LP ^[47][48][73,74], and lichen nitidus ^[49][75], have also been reported in association with ICIs. The detailed pathogenesis of ICI-induced lichenoid eruption remains unclear. However, it is believed that blocking the PD-1/PD-L1 pathway may enhance inflammatory reactions by activating the immune system, such as cytotoxic T cells and APCs. Prominent interferon-γ (IFN-γ) production in patients with oral LP receiving PD-1 inhibitors was found in a previous report ^[50][76]. Another study revealed increased mRNA expression of IFN-γ and granzyme B after anti-PD-1 agent treatment ^[51][77]. In addition, the expression of PD-L1 in keratinocytes has been speculated to play a protective role against cytotoxic T cells in a murine model. Furthermore, MHC-class-II molecule expression on keratinocytes induced by IFN-γ was also noted in a previous paper ^[52][78]. Based on these findings, it is hypothesized that inhibition of immune checkpoints may facilitate antigen presentation and lead to damage of basal epidermal keratinocytes through the activation of autoreactive cytotoxic T cells, which are mediated by IFN-γ and other molecules ^[53][79]. Gene expression profiles and immune compositions of ICI-related lichenoid eruption have also been analyzed previously. One study reported increased CD14+ and CD16+ monocytes and upregulation of toll-like receptor 2 (TLR 2) and TLR4 in patients with ICI-induced lichenoid dermatitis. Additionally, study also found higher numbers of T-Bet+ (Th1) cells and lower numbers of Gata-3+ (Th2) cells and FoxP3 (T regulatory) cells in the immune profiles of lichenoid eruptions. These findings suggest that the innate immune response may also be involved in the initiation of lichenoid eruptions through the CD14/TLR signaling pathway ^[54][80].

3.4. Psoriasiform Eruptions

Psoriasiform eruptions are more frequently observed in patients receiving PD-1/PD-L1 inhibitors than in patients receiving CTLA-4 inhibitors. Approximately 3–12% of patients treated with PD-1 inhibitors may be affected ^{[13][14][55][56]}[13,14,81,82]. These eruptions can be categorized into two types, including newly onset psoriasis (de novo psoriasis) and a flare-up of pre-existing psoriasis (reactivated psoriasis). A previous report revealed that out of 115 cases of ICI-induced psoriasis, 70% of patients developed de novo psoriasis, while 30% had a history of psoriasis ^[57][83]. The lesions commonly appear after three to twelve weeks of treatment ^[10][12][10,12], with an average onset time of about fifty days for psoriasis flare-ups and about ninety-one days for newly developed psoriasis ^[55][81]. The most common type of ICI-induced psoriasiform eruption is plaque psoriasis, characterized by erythematous silvery scaly plaques with well-defined borders localized on the extensor surfaces of extremities and the trunk. Less frequent variants, including palmoplantar, pustular, guttate, and inverse psoriasis, have also been reported previously ^[57][83]. Histopathological findings resemble typical psoriasis vulgaris, with features such as parakeratosis, hypogranulosis, acanthosis with elongated rete ridges, and a perivascular lymphocytic infiltration ^[10][13][37][10,13,63]. Moreover, compared to typical psoriasis, variable spongiosis, infiltration of eosinophils, and lichenoid change can also be found in ICI-related psoriasis ^[58][59][84,85]. In the general population, psoriasis is mainly driven by the activation of the Th17 pathway, and several cytokines, including tumor necrosis factor alpha (TNF-α), IL-23, IL-17, and IL22, play important roles in its pathogenesis ^[60][86]. The detailed mechanisms underlying ICI-induced psoriasiform eruptions are still unclear. However, studies in animal models have shown that blocking immune checkpoint molecules can result in enhanced production of IL-17A and IL-22 via activated T cells, either through gene silencing or monoclonal antibody treatment. Based on these findings, it is hypothesized that ICIs may lead to the overproduction of proinflammatory cytokines, mediated by activated Th17 cells, which in turn promote neutrophil recruitment and keratinocyte hyperproliferation, ultimately exacerbating or inducing psoriasis. In patients, psoriasis is frequently associated with obesity and imbalanced dietary habits ^[61][87]. In a murine model system, it has been observed that the consumption of a Western diet (WD) high in fat and simple sugars dramatically increases the expression of PD-1 on γδ low (GDL) T cells, which are the main producers of IL-17A, thereby exacerbating the psoriasiform dermatitis induced by imiquimod (IMQ). Additionally, mice fed a WD and exhibiting obesity demonstrate a greater severity of IMQ-induced psoriasiform dermatitis compared to control mice when administered anti-PD1 treatment. Based on these findings, it is hypothesized that WD-induced obesity may be involved in the development of de novo psoriasis-like skin lesions or the worsening of pre-existing psoriasis in patients undergoing anti-PD-1 therapy, although the exact mechanism remains unknown ^[62][63][88,89].

3.5. Vitiligo-like Depigmentation

Vitiligo is an autoimmune disease characterized by the presence of well-defined, depigmented macules or patches resulting from the loss of functional melanocytes in the epidermis ^[64][65][66][90,91,92]. Among the various types of cutaneous irAEs, vitiligo-like depigmentation (VLD) is a subtype that occurs as a result of reactive autoimmunity targeting melanocytes in normal tissues during immunotherapy. VLD is more frequently observed in patients with advanced melanoma, while its occurrence in other malignancies is relatively rare ^{[65][67][68][69]}[91,93,94,95]. Compared to anti-CTLA-4 therapy, VLD is more often induced during anti-PD-1 therapy, with incidence rates ranging from 7–11% and 2–9%, respectively. Moreover, the lesions commonly develop between seven and sixty-five weeks after starting ICI therapy, with a median onset time of approximately twenty-six weeks, and these lesions often persist even after discontinuation of immunotherapy ^[11][12][70][11,12,96]. Despite the significant psychosocial impact, the occurrence of VLD during ICI therapy is significantly associated with a favorable prognosis in patients with melanoma, including prolonged progression-free survival and overall survival rates ^[71][97]. This correlation highlights the strong relationship between irAEs and enhanced antitumor activity ^{[10][64][65][71]}[10,90,91,97]. The clinical manifestations of ICI-induced VLD differ from those of idiopathic vitiligo, which tends to occur more commonly in periorificial areas and acral surfaces. VLD is characterized by the presence of multiple flecked macules that evolve into larger patches, predominantly affecting sun-exposed areas in a symmetrical pattern. Unlike idiopathic vitiligo, VLD is not associated with the Koebner phenomenon ^[72][98]. Moreover, an inflammatory phase may precede the development of depigmented lesions in VLD ^[27][65][53,91], and depigmentation of the skin may coincide with poliosis of the eyelashes and scalp hair ^[17][27][43,53]. Histologically, VLD shows an inflammatory infiltrate in the dermis primarily composed of T cells and a lack of melanocytes. The exact pathogenesis of immunotherapy-induced VLD remains uncertain, but several studies have proposed that its development is related to cross-reactivity against shared antigens present on both melanocytes and tumor cells. Upon treatment with anti-PD-1 agents, skin depigmentation occurs as a result of cytotoxic T cell activation against these shared antigens, which include Melanoma antigen recognized by T cells 1 (MART-1, also called Melan-A), GP100, tyrosinase-related proteins 1 and 2 (TRP1 and TRP2), and tyrosinase ^[71][73][97,99]. Immunohistochemical staining analysis has further revealed the presence of CD4 and MART-1/Melan-A specific CD8 T cells in close proximity to apoptotic melanocytes, indicating that anti-CTLA-4 antibodies may also contribute to stimulating an immune reaction against melanocytes ^[74][100].

3.6. Autoimmune Bullous Disease

Compared to other cutaneous irAEs, autoimmune bullous disorders are relatively less frequently observed. The incidence of ICI-induced bullous diseases is approximately 1% in patients treated with PD-1/PD-L1 inhibitors ^[12][13][75][12,13,101], and the onset time is typically between thirteen and eighty weeks after initiating immunotherapy, which is longer than other cutaneous irAEs ^[12][76][77][12,102,103]. Among the bullous diseases associated with immunotherapy, bullous pemphigoid (BP) is the most common presentation, followed by bullous lichenoid dermatitis and linear IgA bullous dermatosis ^[75][101]. The clinical presentations of ICI-induced BP resemble classic BP, characterized by a pruritic prodromal non-bullous phase followed by the development of tense bullae filled with serous or hemorrhagic fluid mainly localized on the trunk and extremities. Other variants, such as urticarial-predominant, eczematous rash, Grover disease–like, and dyshidrosiform, have also been reported previously ^[27][78][53,104]. However, unlike idiopathic BP, mucous membrane involvement is more common, with a frequency of up to 40% ^[38][79][64,105]. Histopathological findings are similar to those of spontaneous BP, which show subepidermal blisters with numerous eosinophils, and direct immunofluorescence reveals linear deposition of complement component 3 (C3) and immunoglobulin G (IgG) along the basement membrane zone ^[10][13][80][10,13,106]. It is believed that autoimmune bullous disorders induced by PD-1/PD-L1 inhibitors involve both T cell and B cell dysregulation. In T cell-independent humoral immunity, PD-1/PD-L1 blockades can enhance B-cell activation, leading to the production of disease-specific autoantibodies. These autoantibodies are responsible for cross-reactive immunogenicity against basement membrane proteins BP180 and BP230, which are expressed on certain cancer cells (such as melanoma and non-small cell lung carcinoma) as well as normal skin, thereby inducing BP ^{[42][80][81][82]}[68,106,107,108]. In T cell-dependent humoral immunity, PD-1 acts as an activator for B cells interacting with either follicular helper T cells (Tfh) or follicular regulatory T cells (Tfr) within the germinal centers. Tfh cells play a role in the selection and survival of B cells, enabling their differentiation into memory B cells or high-affinity antibody-producing plasma cells. On the other hand, Tfr cells maintain immune balance by suppressing both Tfh cells and B cells. Inhibition of PD-1 may reduce the suppressive ability of Tfr cells and lead to potentially mutated B cells selected by Tfh cells. This can result in an aberrant production of low-affinity plasma cells, which contribute to the development of numerous antibody-mediated autoimmune disorders, including BP ^[81][107]. In addition to cross-reactivity, the production of autoantibodies against different epitopes, which is termed epitope-spreading phenomena, has also been observed in anti-PD-1/PD-L1-associated BP ^[81][107]. It has been reported that host genetic background may also be important in their susceptibility to irAEs, and several genetic variants associated with irAEs have been identified recently ^[83][109]. One SNP associated with an increased risk of autoimmune bullous pemphigoid has been linked to the DSC2 gene ^[84][110].

3.7. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis-like Reaction

ICI-related SCARs, such as SJS/TEN-like reactions, are rare dermatologic toxicities, but they can be potentially life-threatening ^{[85][86][87][88]}[111,112,113,114]. The onset time of SCARs varies from one to twenty weeks after initiation of immunotherapy ^[12][89][12,115], and the mortality rates are approximately 10% for SJS, 30% for SJS-TEN overlap syndrome, and 50% for TEN, respectively ^[79][89][90][105,115,116]. The clinical presentations are similar to classical SJS/TEN, including fever, conjunctival injection, and malaise, followed by diffuse erythema, with or without targetoid lesions on the trunk and extremities, progressing to flaccid bullae with a positive Nikolsky sign. In addition, mucosal involvement of the conjunctivae, oral cavity, gastrointestinal tract, respiratory tract, and genitalia may be observed ^[20][91][46,117]. However, unlike classical SJS/TEN, the SJS/TEN-like eruption has a longer onset time and the symptoms are usually milder than typical SJS/TEN, with less ocular involvement and less denuded skin. It has also been found that a morbilliform eruption may precede the ICI-induced SJS/TEN-like reactions. Therefore, it is important to closely monitor patients with a morbilliform rash for red-flag signs, such as blister formation, a positive Nikolsky sign, development of targetoid lesions, skin pain or mucosal involvement ^[92][118]. Histopathological findings show full-thickness epidermal necrolysis with extensive keratinocyte necrosis, subepidermal bullae, and a varied degree of inflammation in the superficial dermis with a sparse dermal infiltrate. Some studies speculate that the inhibition of checkpoint molecules interferes with the balance between the peripheral tolerance and the function of keratinocytes in protecting against damages, which eventually explains the frequent ICI-induced cutaneous eruptions. It has been found that PD-L1 is usually undetectable in normal skin, but ICI treatment can stimulate PD-L1 expression, triggering apoptosis of PD-L1 expressing keratinocytes induced by activated cytotoxic T cells ^[12][93][12,119]. Moreover, ICI-induced SJS/TEN-like eruptions exhibit a similar gene expression profile to classical SJS/TEN, both of which show increased expression of inflammatory chemokines, cytotoxic mediators (such as perforin and granzyme B), and apoptosis-promoting molecules (such as Fas Ligand). It is believed that, similar to morbilliform rash, type IVc hypersensitivity may also be involved in SJS/TEN-like reactions ^[12][89][94][12,115,120]. Furthermore, the enhancement of co-stimulatory factors and dysfunction of Treg cells are also associated with SJS/TEN pathogenesis [12].